COMMENT & RESPONSE
Deaths and Cardiovascular Events in Men Receiving Testosterone Abraham Morgentaler, MD1; Abdulmaged Traish, PhD2; Ravi Kacker, MD1
JAMA. 2014;311(9):961-962. doi:10.1001/jama.2014.392.
To the Editor As clinicians and researchers in the testosterone field, we found surprising the results reported by Dr Vigen and colleagues 1 of increased deaths and cardiovascular events in male veterans receiving testosterone following coronary angiography because these results contradict a literature spanning more than 20 years. 2Should testosterone therapy be considered unsafe based on this study? We do not believe so.
This study was not a straightforward 2-group comparison in which there were a higher number of events in men who received testosterone. Rather, this was a complex retrospective study with a messy data set, containing a serious flaw that distorted the conclusion.
The authors wrote, “… the Kaplan-Meier estimated cumulative percentages with events were 19.9% in the no testosterone therapy group vs 25.7% in the testosterone therapy group …” at 3 years following coronary angiography. However, we note the raw rate of events in the testosterone group was only 10.1% (123 events in 1223 men) compared with 21.2% (1587 events in 7486 men) in the no testosterone group. The authors neither acknowledged these data favoring the testosterone group, nor did they explain what drove results to an opposite conclusion.
The Kaplan-Meier curves are similarly misleading because the approximately 30% event rate for the testosterone group at the end of the study is a 3-fold multiple of the actual event rate. We assume the disparity is derived from calculated estimates based on statistical adjustment for more than 50 variables, thus magnifying potential errors.
Both groups began as a single population, with men joining the testosterone group as they began treatment, thus contributing to both event curves. A myocardial infarction was attributed to the testosterone group if a man filled his testosterone prescription the same day, but to the no testosterone group if he had not yet filled his prescription. This does not make sense.
In addition, basic information was not provided. Did time zero begin for the testosterone group at angiography or testosterone initiation? Could raw event data be provided for years 1 to 3? What was the mean time to events after receiving testosterone therapy? What were the person-years of exposure for both groups?
Our greatest concern is that 1132 men with myocardial infarction or stroke who subsequently received testosterone were incorrectly excluded from the study. It was irrelevant what happened after their event. All these events should have been included in the no testosterone group, increasing the number of events by 71%, thereby yielding an outcome consistent with 2 recent studies, 3 4 and demonstrating a reduction in mortality with testosterone therapy.
Article Information Corresponding Author: Abraham Morgentaler, MD, Harvard Medical School, One Brookline Place, Ste 624, Brookline, MA 02467 (firstname.lastname@example.org).
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Morgentaler reported receiving grants and personal fees from Auxilium; grants from Antares and Lilly; and personal fees from Bayer, Merck, and AbbVie. 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.PubMed
2 ↵ Traish AM, Miner MM, Morgentaler A, Zitzmann M. Testosterone deficiency. Am J Med. 2011;124(7):578-587.PubMed
3 ↵ Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012;97(6):2050-2058.PubMed
4 ↵ Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. 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(6):725-733.PubMed