Summary Points
-
FDA is re-evaluating safety of testosterone replacement therapy.
-
Two recent cohort studies showed an increased risk for myocardial infarction and stroke when taking testosterone replacement therapy.
-
Higher relative risk is seen mainly in older men with underlying coronary artery disease.
-
Current studies have been retrospective or have had a small sample size; therefore, large randomized trials are required.
By German Rodriguez, MD
Attending Physician, West Park Medical Group, New York, NY
Dr. Rodriguez reports no financial relationships relevant to this field of study.
Synopsis: Two recent cohort studies showed an increased risk for myocardial infarction and stroke when taking testosterone replacement therapy.
Sources: Vigen R, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310:1829-1836.
Finkle WD, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014;9:e85805.
The prescription rate of testosterone therapy has increased dramatically in the last decade,1 and primary care practitioners are asked on a daily basis about testosterone supplementation. Ingenious marketing has led many patients — many of whom are older and have risk factors for heart disease — to question if testosterone therapy is right for them.2
Until recently, there were very few studies looking into the potential risks of testosterone therapy.3 In January 2014, the FDA issued a warning and stated that it was re-evaluating the effect of testosterone therapy on myocardial infarction (MI), stroke, and death.4 This reassessment is based on two recently published studies, as described below.5,6
Vigen et al Study
This retrospective national cohort study was conducted on men who had their testosterone level checked and were undergoing coronary angiography within the VA hospital system.5 Data were extracted for the period of 2005-2011 from the VA electronic medical record system, VA administrative database, and VA laboratory files. The final cohort included men who had low testosterone (< 300), had never undergone testosterone replacement, and had undergone coronary angiography.
Patients with testosterone therapy use prior to coronary angiography were excluded, as were patients who started testosterone therapy prior to having a testosterone level checked or who were prescribed testosterone therapy after an MI. Patients with a hematocrit > 50%, a prostate-specific antigen > 4.0, or incomplete anatomical angiographic data were excluded.
Patients were considered to have started testosterone therapy if they filled a prescription for any formulation of testosterone after coronary angiogram. It was assumed that patients continued with the treatment until an outcome event occurred or the follow-up period ended. The primary endpoint of the study was time to all-cause mortality or hospitalization for MI or ischemic stroke.
As patients could not be randomized to testosterone therapy, stabilized inverse probability of treatment weighting was used to adjust for any unmeasured confounders that may have affected testosterone prescription. The final cohort was comprised of 8709 men with low testosterone. Of these, 1223 patients initiated testosterone therapy.
There was an overall high rate of comorbidities in the study population, but the patients starting testosterone therapy tended to be younger and have a lower rate of comorbidities.5 Testosterone therapy was started after a median of 531 days and the patients were followed for an average of 27.5 months. The Kaplan-Meier estimated cumulative percentages with primary endpoint events among the no testosterone therapy group vs the testosterone therapy group at 1 year after coronary angiography were 10.1% vs 11.3%; at 2 years, 15.4% vs 18.5%; and at 3 years, 19.9% vs 25.7%. The absolute risk differences were 1.3% (95% confidence interval [CI], -7.1% to 9.7%) at 1 year, 3.1% (95% CI, -4.9% to 11.0%) at 2 years, and 5.8% (95% CI, -1.4% to 13.1%) at 3 years. There were no statistically significant differences between groups at any follow-up period except for a history of cerebrovascular disease.
Finkle et Study
This was a cohort study examining the risk of acute non-fatal MI following an initial testosterone therapy prescription in the Truven Health MarketScan Commercial Claims and Encounters Database.6 This database includes all health data licensed to Truven from fortune 500 companies, unions, and many other employers. Data from the period of 2006-2010 within the northeastern, north central, southern, and western United States was initially analyzed. Information related to why testosterone was prescribed was not available.
The investigators formed two cohorts from men who were enrolled in the database for a minimum of 22 continuous months. These groups were divided into men who had filled a prescription for testosterone and men who filled a prescription for phosphodiesterase type 5 inhibitors. The latter medication class was chosen as a comparison because it tends to have similar indications as testosterone, these medications are commonly prescribed in older men, they do not have androgenic effects, they are not metabolized to a sex steroid hormone, and they have not been associated with adverse cardiovascular events.
The investigators compared the incidence rate of MI in the 90-day period following the initial prescription with the rate in the 1 year prior to the initial prescription of testosterone therapy. They also compared post-/pre-rates in a cohort of men prescribed phosphodiesterase type 5 inhibitors. Testosterone supplementation post-/pre-rates were compared with phosphodiesterase type 5 inhibitors post-/pre-rates. The main outcome of the study was acute MI. Patients with a history of MI prior to the initial prescription were excluded.
In this study, the adjusted rate ratio (RR) of myocardial infarction in patients prescribed testosterone therapy was 2.19 (95% CI, 1.27-3.77) in patients older than age 65 years and 1.17 in patients younger than age 65 years (95% CI, 0.84-1.63). By age, the RR was 0.95 (95% CI, 0.54-1.67) in patients under 55 years, 1.35 (95% CI, 0.77-2.38) in patients 55-59 years, 1.29 (95% CI, 0.71-2.35) in patients 60-64 years, 1.35 (95% CI, 0.44-4.18) in patients 65-69 years, 1.62 (95% CI, 0.51-5.16) in patients 70-74 years, and 3.43 (95% CI, 1.54-7.66) in patients older than 75 years. (P trend = 0.03).
The phosphodiesterase 5 inhibitor group baseline distribution of prior cardiovascular diagnosis, risk factors, and medication use was less than in the testosterone therapy group. This was adjusted with weighting with propensity scores. When comparing the testosterone therapy group to the phosphodiesterase 5 inhibitor group, the rate ratio was 1.90 (1.04-3.49) in those older than age 65 years and 1.10 (95% CI, 0.78-1.56) in those younger than age 65 years.
In men younger than age 65 years with a previous history of heart disease who were prescribed testosterone, the RR was 2.90 (95% CI, 1.49-5.62) vs 0.90 (95% CI, 0.61-1.34) for those without a previous history of heart disease. In men prescribed testosterone therapy who were older than age 65 years, the RR was 2.16 (95% CI, 0.92-5.10) for those who had a history of heart disease and 2.21 (95% CI, 1.09-4.45) for those without a history of heart disease. In men with a history of heart disease who were prescribed phosphodiesterase 5 inhibitors, the RR was 1.40 (95% CI, 0.91-2.14) for those younger than age 65 years and 0.99 (95% CI, 0.84-1.17) for those older than age 65 years.
Commentary
Testosterone replacement therapy is a common topic of discussion with middle-aged and older men. When abstracts of relevant articles spread through the medical media, many of us believed the results were going to change our practice. This thought seemed to be solidified by the fact that the FDA was further investigating the risk of cardiovascular events and death based on the two studies reviewed here. Now that we have been able to thoroughly look through these articles, what conclusions can be drawn?
In both studies the risk of myocardial infarction, stroke, and death was higher in the groups that were given testosterone replacement therapy. In the study by Finkle et al, there seemed to be an age-dependent effect, as the risk was higher in older men, with a trend of increased risk across age categories. This risk was even higher in older men with underlying cardiovascular disease.
The studies are based on data retrieved retrospectively, predisposing them to confounding and selection bias. Crucial clinical information is missing because of the study design. For example, we do not know if any of the study subjects met clinical criteria for hypogonadism, the time at which the samples were drawn, whether the results were confirmed by a second sample, and if any of the samples were obtained while a patient was ill. Follow-up information related to post-treatment testosterone levels, adherence levels, and clinical response was also poor. The pooled information was analyzed using complex computer models that could potentially increase hidden bias.
Proponents of testosterone replacement therapy might point out that there are studies which have found differing results:
-
In 2012, one retrospective study investigated data from the VA medical records for 1031 patients.7 It was found that mortality was lower in men who were treated with testosterone compared with those who did not receive replacement therapy. The results may differ from the two studies analyzed due to the small sample size, no standardized time of testosterone testing, multiple testosterone formulations were utilized, and the main outcome was total mortality. There was a high rate of medical morbidity, with an average of 6.7 pharmacologically treated conditions. This included a 38% rate of diabetes mellitus and 21% rate of coronary heart disease. This means that a majority of the study participants did not have a history of prior coronary heart disease and, based on the results found by Vigen and Finkle et al, are at decreased risk from testosterone replacement.
-
Other studies have found that men who have endogenous testosterone concentrations in the middle to higher normal range have the lowest mortality and least likelihood of having a cardiovascular event.8,9 These same studies have also found that men who have low testosterone have an increased risk for cardiovascular events. Dogan et al also showed an inverse correlation between testosterone levels and atherosclerosis markers.8 We can conclude that low testosterone is bad and normal testosterone levels are beneficial. Should we offer replacement therapy for all patients with low levels? Not necessarily. The studies reviewed show that currently available testosterone formulations may not be safe for everyone.
On the other hand, multiple studies have established that there is a normal age-related decline in testosterone levels,10,11 and there is no consensus as to the exact cutoff for low testosterone. This is why currently available guidelines only recommend testosterone replacement for those who meet criteria for symptomatic hypogonadism. In my opinion, this means we should have a discussion about treatment outcome expectations and lifestyle modification prior to considering replacement therapy.
In summary, the data are conflicting and confusing.12 Large, prospective, randomized trials are required before a valid consensus can be drawn, a consensus upon which we can frame our clinical practice. Until that time, many of our questions will not be adequately answered and, therefore, we are at the mercy of expert opinion.
One approach to navigate this uncertainty is by having an open conversation with our patients. Testosterone should only be measured in those who meet clinical criteria for hypogonadism. We should inform them that low testosterone levels may increase the risk of coronary heart disease and normal endogenous levels may decrease the risk of coronary heart disease. We do not yet know, with certainty, what impact exogenous testosterone may have, as some studies have shown benefit and others have shown increased risk, especially in those older than age 65 years and those with a prior history of coronary heart disease, regardless of age. Patients should be aware of normal decline in testosterone levels related to age, as well as other normal age-related changes that could erroneously be attributed to low testosterone. Some patients may opt for a holistic approach that embraces lifestyle modification in lieu of testosterone replacement. We should advise patients on the benefits of a healthy weight, routine exercise, adequate sleep, avoiding tobacco products, limiting alcohol, stress management, and healthy eating.
Until more information is available, we can cautiously continue to offer testosterone replacement therapy in those who meet diagnostic criteria of hypogonadism after a thorough discussion about its potential risks and benefits.
References
1. Baillargeon J, et al. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med 2013;173:1465-1466.
2. Layton JB, et al. Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011. J Clin Endocrinol Metab 2014;99:835-842.
3. Grech A, et al. Adverse effects of testosterone replacement therapy: An update on the evidence and controversy. Ther Adv Drug Saf 2014;5:190-200.
4. U.S. Food and Drug Administration. FDA Drug Safety Communication: FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm383904.htm. Accessed Nov. 1, 2014.
5. Vigen R, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013;310:1829-1836.
6. Finkle WD, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014;9:e85805.
7. Shores MM, et al. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012;97:2050-2058.
8. Do?an BA, et al. Effect of androgen replacement therapy on atherosclerotic risk markers in young-to-middle-aged men with idiopathic hypogonadotropic hypogonadism. Clin Endocrinol (Oxf) 2014; Oct 3 [Epub ahead of print].
9. Muraleedharan V, et al. Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol 2013;169:725-733.
10. Mohr BA, et al. Normal, bound and nonbound testosterone levels in normally ageing men: Results from the Massachusetts Male Ageing Study. Clin Endocrinol (Oxf) 2005;62:64-73.
11. Wu FC, et al. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab 2008;93:2737-2745.
12. Morgentaler A. Testosterone, cardiovascular risk, and hormonophobia. J Sex Med 2014;11:1362-1366. doi: 10.1111/jsm.12556. Epub 2014 May 2.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content
Already have an account? Log in