Testosterone Therapy After Angiography Linked to Increased Cardiovascular Risk
Introduction: While rates of testosterone supplementation are rising in the United States, the impact of this therapy on cardiovascular outcomes is unclear. A previous study—the Testosterone in Older Men with Mobility Limitations (TOM) trial—raised concerns about the safety of this therapy.
Methods: The retrospective national cohort study included 8,709 men who underwent coronary angiography in the Veterans Affairs (VA) system between 2005 and 2011 and met Endocrine Society guideline criteria for testosterone replacement (ie, testosterone level <300 ng/dL; normal hematocrit and prostate-specific antigen levels). The men had not taken testosterone therapy in the past. The cohort had a high rate of comorbidities including myocardial infarction (20%), diabetes (50%), and coronary artery disease (CAD; 80%).
Of the overall group, 1,223 (14%) began taking testosterone therapy after a median time of 531 days following angiography. The primary outcome measure was a composite of all-cause mortality, myocardial infarction, and ischemic stroke over an average follow-up of 27.5 months.
Results: One-quarter of the testosterone therapy group (25.7%) experienced events 3 years after coronary angiography compared with 19.9% of the group that did not receive testosterone therapy, for an absolute risk difference of 5.8%.
Even after adjusting for other potentially confounding variables in Cox proportional hazards models, use of testosterone therapy was associated with adverse outcomes (hazard ratio, 1.29) and was consistent among patients with and without CAD.
Conclusion: Use of testosterone therapy was associated with increased risk of mortality, myocardial infarction, or ischemic stroke in men who underwent coronary angiography and had a low serum testosterone level.
Vigen and colleagues reported an increased incidence of adverse cardiovascular events in men on testosterone therapy, using retrospective analysis of large national cohort (VA system). No difference was seen between men with CAD and those without. No difference was seen based on route of testosterone administration in subanalysis; however, only 1.1% (13/1,223) used testosterone gel, with 35.7% receiving injections and 63.3% using the patch.
In considering the implications for use of testosterone in aging, this cohort includes a relevant age range, with a mean age 60.6 years in the testosterone therapy group and 63.8 years in the non-testosterone group. Unsurprisingly, the group that initiated testosterone had a lower mean testosterone level at baseline (175.5 ng/dL vs. 206.5 ng/dL).
This is the first observational study that reports increased CAD morbidity/mortality in men using testosterone. Previous clinical trials, with one notable exception (the TOM trial1)—have not shown adverse cardiovascular effects, although these tend to represent smaller studies. The TOM trial was a randomized clinical trial of men age ≥65 years; after an increase in cardiovascular adverse events was noted in the group randomized to testosterone versus placebo, the trial was stopped before enrollment was complete.2
Results differ from a recent retrospective VA study by Shores and colleagues;3 this difference may be related to the particular cohort, as the cohort studied by Vigen et al had more baseline cardiovascular morbidity and was culled from a group undergoing coronary angiography. The generalizability of these results remains to be seen, via further studies.
Of note, the study by Vigen et al is not a randomized clinical trial, and has limitations inherent in a retrospective observational study. In fact, it was in part the cardiovascular adverse event signal in the TOM trial that led Vigen et al to investigate this topic using the VA database, according to one of the primary investigators.4 In addition, this study used a composite endpoint, of all-cause mortality, MI, and ischemic stroke, as the primary outcome. Finkle et al more recently published a study looking specifically at myocardial infarction risk in a general healthcare database (also reviewed in this issue of EndoScan).
The authors did take steps to limit some of the biases and pitfalls inherent in observational studies (eg, time-varying treatment-selection bias, immortal time bias, residual confounding) via stabilized weights method and ancillary analyses. However, as they themselves note, there may be confounders that were not measured. As with other observational trials, it is unclear what time of day testosterone levels were drawn; the role of baseline lower testosterone levels and the rationale for initiating testosterone replacement are unclear.
This study underscores the importance of discussing with one’s patients the potential risks as well as the benefits of testosterone replacement, as well as the current lack of consistent safety evidence from randomized clinical trials.
1. Boloña ER, Uraga MV, Haddad RM, et al. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007;82(1):20-28.
2. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. 2010;363(2):109-122.
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.
4. O'Riordan M. Testosterone therapy linked with adverse CVD events. Medscape. November 5, 2013.