Deaths and Cardiovascular Events in Men Receiving Testosterone James Katz, MD, MPH1; Robert Nadelberg, MD1

JAMA. 2014;311(9):963. doi:10.1001/jama.2014.395.

[+]Author Affiliations

To the Editor Dr Vigen and colleagues 1 found an association between testosterone therapy and increased cardiovascular events. We believe what they actually demonstrated was failure to follow guidelines 2 from the Endocrine Society, which resulted in suboptimal patient outcomes. In addition, the authors used statistics that obscure rather than illuminate.

The testosterone treatment group was inadequately screened for hypopituitarism. The treatment group had a mean testosterone level of 175.5 ng/dL at baseline. The Endocrine Society recommends pituitary evaluation at levels below 150 ng/dL. One might suspect that among the 1223 treated patients, some had values below 150 ng/dL and these patients should have been excluded.

The treatment group received inadequate treatment. The Endocrine Society recommends the target of 400 to 500 ng/dL with testosterone supplementation. The treatment group had a mean testosterone level after treatment of only 332.2 ng/dL.

The treatment group received inadequate follow-up. The Endocrine Society recommends retesting of testosterone and hematocrit levels 3 months after initiation of therapy. Only 60% of the treatment group had their testosterone levels retested at all during follow-up. Even though Vigen et al 1 discussed the risks of platelet thromboxane A2receptor density and platelet aggregation, retesting of hematocrit was not discussed. Polycythemia occurs in up to 40% of patients receiving androgen treatment. 3 Failure to monitor hematocrit could lead to increased cardiovascular events.

The methods for calculating the weighting of incidents from the number of incidents is unclear. The authors do not explain how their use of “stabilized inverse probability” can change a decreased crude event rate into an increased rate as stated in the study. The Kaplan-Meier curves cross near their origin, indicating a nonproportional hazard, which the authors ignored. I suspect the cause of the early mortality may be that the decision to treat patients was not random, which no amount of retrospective statistical manipulation can fix.

Testosterone therapy has risks, but this study does not make the case for these outcomes being significant.

Article Information Corresponding Author: James Katz, MD, MPH, Age Management Boston, 20 Park Plaza, Ste 473, Boston, MA 02116 (

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none 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.PubMed

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.PubMed

3 ↵ Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA. Pharmacokinetics, efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab. 1999;84(10):3469-3478.PubMed

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