Prescribing Testosterone Therapy May Increase Risk of Cardiovascular Complications

Review

Vigen R, O’Donnell C, Baron A, Grunwald G, Maddox T, Bradley S, Barqawi A, Woning G, Wierman M, Plomondon M, Rumsfeld J, Ho M. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17):1829-36. http://jama.jamanetwork.com/article.aspx?articleid=1764051.

Study Methods

This retrospective cohort study examined the medical records of 8,709 male patients with low testosterone who underwent cardiac catheterization at hospitals in the US Veterans Affairs (VA) system between 2005 and 2011.

The investigators used the VA Clinical Assessment Reporting and Tracking (CART) program to compare outcomes between patients who initiated testosterone supplementation after their initial catheterizations with those who did not take the drug after catheterization.

Patient outcomes defined by the ICD-9 codes for myocardial infarction (MI), stroke, or any other cause of death were compared between the 2 groups and used to estimate percent survival at 500, 1,000, 1,500, and 2000 days after testosterone treatment initiation.

Patient Demographics

Participants were male veterans with a mean age between 60 and 63 years who underwent coronary angiography, had low levels of serum testosterone (<300 ng/dL), and had never previously used any form of testosterone treatment. Patients were excluded if they had taken testosterone after MI or had hematocrit >50% or a prostate-specific antigen (PSA) level >4 ng/mL.

With the exception of lower mean diastolic blood pressure in the testosterone-treated group compared to control subjects after 2 years of testosterone supplementation, the authors found age, presence of coronary artery disease (CAD), blood pressure, and cholesterol levels were not significantly different between the 2 groups. Of the 8,709 men studied, 20% had a history of MI, 50% had diabetes, and >80% had CAD, which was defined as >20% stenosis of one or more epicardial vessels.

Intervention and Control

Using data from the VA pharmacy dispensary, patients were assigned to the intervention group if they filled at least one prescription for testosterone gel, patch, or injection after a median of 531 days post-coronary catheterization. Of the 1,223 patients in the intervention group, 13 (1.1%) were prescribed the gel, 436 (35.7%) received the injections, and 774 (63.3%) used a testosterone patch. However, there was no significant difference in risk of adverse outcomes between the formulations.

The study’s primary combined endpoint was time to all-cause death or hospitalization for MI or stroke.

Results and Outcomes

After 3 years, 25.7% of those receiving testosterone therapies had an adverse cardiovascular (CV) outcome compared to 19.9% of those who did not receive testosterone. Testosterone use was also associated with increased risk of adverse outcomes, including all-cause mortality, MI, and ischemic stroke. The findings remained unchanged after adjusting for the presence of CVD.

Conclusion

Men with known CVD who receive testosterone therapy experience an increased risk of death, stroke, and heart attack.

Commentary

Testosterone prescriptions have increased 5-fold over the last decade and are now widely administered for a variety of indications that include belly fat, low energy, diminished sex drive, and high cholesterol. Despite the widespread use of testosterone therapies, there remains some speculation concerning their long-term effects on overall health.

Previous investigations into the safety and efficacy of testosterone treatment have been small with short durations, and many of these studies have found conflicting data. This VA study followed patient outcomes for 3 years and then used the data to extrapolate 2,000-day survival curves.

A limitation of this study is its retrospective approach and modeling, which can only suggest a potential risk of testosterone use for those with known CVD. Other concerns include the weight adjusting protocol, which may overemphasize the influence of an adverse event rate, the potential inconsistency of testosterone measurement, the variety of testosterone formulations used, and the possible bias of outcomes based on reported ICD-9 coding, rather than chart audit.

Perhaps the most perplexing component is the raw data included in the publication implies a lower CVD risk in the testosterone group, which contradicts the paper’s conclusion. This prompted many letters to the editor,¹ including a request to retract the paper, which resulted in a detailed response by the authors admitting significant discrepancies.

Despite its popularity among prescribers, testosterone therapy has conflicting data to support its clinical use. The treatment has been recommended to improve mood, sexual function, and satisfaction when used for at least 6 months, and yet larger, more robust studies indicate men taking testosterone therapy have no significant increase in libido, overall sexual satisfaction or erectile function.

Additionally, a 2013 systematic review and meta-analysis found a discrepancy of benefits and adverse outcomes based upon a testosterone study’s source of funding.² Among studies on testosterone therapy that were not funded by the pharmaceutical industry, the risk of a CV-related event was greater.

Testosterone therapy also has considerable side effects, which include gynecomastia, increased prostate volume, erythrocytosis, and inducing or worsening obstructive sleep apnea (OSA) in those with congestive heart failure (CHF).

Future research by unbiased researchers is needed and should include:

• Studies on males with and without known CVD that span across a variety of CV risk factors.
• Comparison studies on a variety of testosterone formulations.
• Study outcomes on clinically relevant endpoints, including greater quality of life, longevity, and all-cause mortality.

The controversy surrounding testosterone therapy should give providers pause when using such treatment in patients at high risk of CVD. The outcome data on testosterone’s benefit for low libido and erectile dysfunction are conflicting and offer worrisome risks.

Until there is clarity, only prescribe testosterone for patients with low total serum testosterone <8 nmol/L (230 ng/dL) or serum free testosterone <225 pmol/L (65 pg/mL) who have clinical signs and symptoms of testosterone deficiency, including osteoporosis, decreased muscle mass or strength, impaired cognition, or classical androgen deficiency syndromes.

References

1. Mogentaler A, Traish A, Kacker R. Deaths and cardiovascular events in men receiving testosterone. JAMA. 2014;311(9):961-2.

http://jama.jamanetwork.com/article.aspx?articleid=1835495.

2. Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med. 2013 Apr 18;11:108. http://www.ncbi.nlm.nih.gov/pubmed/23597181?dopt=Abstract&otool=umasslib.

About the Authors

Deviney Chaponis, MS IV, is a fourth-year medical student at the University of Massachusetts Medical School (UMMS) in Worcester, MA.

She was assisted in writing this article by Frank J. Domino, MD, Professor and Pre-Doctoral Education Director for the Department of Family Medicine and Community Health at UMMS and Editor-in-Chief of the 5-Minute Clinical Consult series (Lippincott Williams & Wilkins).