Deaths and Cardiovascular Events in Men Receiving Testosterone Daniel M. Riche, PharmD1; William L. Baker, PharmD2; Christian A. Koch, MD, PhD3

JAMA. 2014;311(9):963-964. doi:10.1001/jama.2014.386.

[+]Author Affiliations

To the Editor A retrospective cohort study by Dr Vigen and colleagues 1 evaluated the association between testosterone therapy for men with total testosterone levels of less than 300 ng/dL and a composite outcome (all-cause mortality, myocardial infarction, and stroke). Flaws in the design and population of this study may have affected the validity of the conclusions drawn by Vigen et al. 1

No data were provided on individual components of the composite outcome between groups, limiting the utility of the findings. In addition, a number of covariates were not adequately considered. Smoking was included as a weighted variable for the probability of treatment adjustments but was not specifically reported in each group. Chronic obstructive pulmonary disease was reported but should not be considered an adequate surrogate for smoking, which is a direct predictor of cardiovascular outcomes.

Characteristics of the included population also may affect the results. Only 60% of patients who were prescribed testosterone therapy had another check of testosterone level after starting treatment, with a baseline total testosterone level of 175.5 ng/dL and first repeat testosterone level of 332.2 ng/dL. The clinical practice guideline 2 of the Endocrine Society considers a serum testosterone concentration between 400 ng/dL and 700 ng/dL as gonadal. The percentage of patients reaching gonadal testosterone concentrations and the association of these concentrations with the composite outcome were not reported. In theory, oversupplementation or undersupplementation may be significantly associated with the increased risk of the composite outcome rather than any supplementation.

Baseline hematocrit level and change in hematocrit over time were not reported. If the hematocrit level increases above 45%, whole-blood viscosity increases above normal.3 Many of these men already had risk factors for an increasing hematocrit level, endothelial dysfunction, or abnormal platelet aggregation, including obstructive sleep apnea, chronic obstructive pulmonary disease, and diabetes mellitus. Change in hematocrit may account for the finding, rather than a direct effect of testosterone therapy.

Nearly 1 of every 5 men prescribed testosterone therapy filled only 1 prescription. These men were clearly not receiving long-term therapy. Also, adherence was not reported but is likely to be low. A recent analysis of medical claims revealed that only 34% of patients continue with treatment after 6 months and only 15% continue after 1 year. 4

Article Information Corresponding Author: Daniel M. Riche, PharmD, University of Mississippi School of Pharmacy, 2500 N State St, Jackson, MS 39216 (

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Riche reported serving on speaker’s bureaus for Merck, Janssen, and Boehringer-Ingelheim. No other disclosures were reported.

Section Editor: Jody W. Zylke, MD, Senior Editor.

References 1 ↵ Vigen R, O’Donnell CI, Barón 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 ↵ Bhasin S, Cunningham GR, Hayes FJ, et al; Endocrine Society Task Force. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559.


3 ↵ Wells RE Jr, Merrill EW. Influence of flow properties of blood upon viscosity-hematocrit relationships. J Clin Invest. 1962;41:1591-1598.


4 ↵ Schoenfeld MJ, Shortridge E, Cui Z, Muram D. Medication adherence and treatment patterns for hypogonadal patients treated with topical testosterone therapy: a retrospective medical claims analysis. J Sex Med. 2013;10(5):1401-1409.


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