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Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men
Open accessAbstract
BACKGROUND: An association between testosterone therapy (TT) and cardiovascular disease has been reported and TT use is increasing rapidly. METHODS: We conducted a cohort study of the risk of acute non-fatal myocardial infarction (MI) following an initial TT prescription (N = 55,593) in a large health-care database. We compared the incidence rate of MI in the 90 days following the initial prescription (post-prescription interval) with the rate in the one year prior to the initial prescription (pre-prescription interval) (post/pre). We also compared post/pre rates in a cohort of men prescribed phosphodiesterase type 5 inhibitors (PDE5I; sildenafil or tadalafil, N = 167,279), and compared TT prescription post/pre rates with the PDE5I post/pre rates, adjusting for potential confounders using doubly robust estimation. RESULTS: In all subjects, the post/pre-prescription rate ratio (RR) for TT prescription was 1.36 (1.03, 1.81). In men aged 65 years and older, the RR was 2.19 (1.27, 3.77) for TT prescription and 1.15 (0.83, 1.59) for PDE5I, and the ratio of the rate ratios (RRR) for TT prescription relative to PDE5I was 1.90 (1.04, 3.49). The RR for TT prescription increased with age from 0.95 (0.54, 1.67) for men under age 55 years to 3.43 (1.54, 7.56) for those aged ≥ 75 years (p trend = 0.03), while no trend was seen for PDE5I (p trend = 0.18). In men under age 65 years, excess risk was confined to those with a prior history of heart disease, with RRs of 2.90 (1.49, 5.62) for TT prescription and 1.40 (0.91, 2.14) for PDE5I, and a RRR of 2.07 (1.05, 4.11). DISCUSSION: In older men, and in younger men with pre-existing diagnosed heart disease, the risk of MI following initiation of TT prescription is substantially increased.
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“Some epidemiological studies have reported an increase in cardiovascular mortality related to TRT while others have not been able to establish a correlation between the two [19,20].”
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Treatment of Men for “Low Testosterone”: A Systematic Review
Huo, S., Scialli, A. R., McGarvey, S., Hill, E., Tügertimur, B., Hogenmiller, A., Hirsch, A. I., & Fugh-Berman, A. (2016) · PLOS ONE · doi:10.1371/journal.pone.0162480 · Cited by 97
Khera, M., Broderick, G. A., Carson, C. C., Dobs, A. S., Faraday, M. M., Goldstein, I., Hakim, L. S., Hellstrom, W. J. G., Kacker, R., Köhler, T. S., et al. (2016) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2016.04.022 · Cited by 99
Kaur, H., & Werstuck, G. H. (2021) · CJC Open · doi:10.1016/j.cjco.2021.05.007 · Cited by 98
“Cox proportional hazard models indicated an increased risk of adverse cardiovascular outcomes in men receiving testosterone therapy (HR 1.29 [95% CI 1.04- 1.58]).27 In accordance with these results, a retrospective cohort study by Finkle et al.28 reported a statistically significant elevation of myocardial infarction…”
BackgroundResultInfluentialHackett, G. I., Kirby, M. G., Rees, R. W., Jones, T. H., Muneer, A., Livingston, M. A., Ossei‐Gerning, N., David, J., Foster, J., Kalra, P. A., et al. (2023) · The World Journal of Men s Health · doi:10.5534/wjmh.221027 · Cited by 99
“A retrospective US study [81] involved 8,709 men with a baseline TT of ≤10.”
Testosterone replacement therapy: for whom, when and how?
Tsametis, C. P., & Isidori, A. M. (2018) · Metabolism · doi:10.1016/j.metabol.2018.03.007 · Cited by 96
Comparative Safety of Testosterone Dosage Forms
Layton, J. B., Meier, C. R., Sharpless, J. L., Stürmer, T., Jick, S. S., & Brookhart, M. A. (2015) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2015.1573 · Cited by 96
Sex differences in vascular aging in response to testosterone
Moreau, K. L., Babcock, M. C., & Hildreth, K. L. (2020) · Biology of Sex Differences · doi:10.1186/s13293-020-00294-8 · Cited by 98
Yeap, B. B., Alfonso, H. S., Chubb, S. A. P., Hankey, G. J., Handelsman, D. J., Golledge, J., Almeida, O. P., Flicker, L. A., & Norman, P. E. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-2664 · Cited by 94
Traish, A. M. (2014) · Current Opinion in Endocrinology Diabetes and Obesity · doi:10.1097/med.0000000000000086 · Cited by 95
Why does COVID‐19 kill more elderly men than women? Is there a role for testosterone?
Papadopoulos, V., Li, L., & Samplaski, M. K. (2020) · Andrology · doi:10.1111/andr.12868 · Cited by 94
“Although this treatment does have associated risks (32-37), the indications, treatment, and follow-up for men being treated with T are well-defined and generally considered safe for treatment of male hypogonadism, LOH/functional hypogonadism (25, 38).”
BackgroundHackett, G. I., Heald, A. H., Sinclair, A. J., Jones, P. W., Strange, R. C., & Ramachandran, S. (2016) · International Journal of Clinical Practice · doi:10.1111/ijcp.12779 · Cited by 93
Albert, S. G., & Morley, J. E. (2016) · Clinical Endocrinology · doi:10.1111/cen.13084 · Cited by 91
Adverse effects of testosterone replacement therapy: an update on the evidence and controversy
Grech, A., Breck, J., & Heidelbaugh, J. (2014) · Therapeutic Advances in Drug Safety · doi:10.1177/2042098614548680 · Cited by 81
“A recent cohort study was conducted to assess the risk of acute nonfatal MI within 90 days following an initial prescription for TRT in a healthcare database of 55,593 US men [Finkle et al. 2014].”
Reactive oxygen species: players in the cardiovascular effects of testosterone
Tostes, R. C., Carneiro, F. S., de Carvalho, M. H. C., & Reckelhoff, J. F. (2015) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00392.2014 · Cited by 90
Sex-Specific Cardiovascular Risks of Cancer and Its Therapies
Wilcox, N. S., Rotz, S. J., Mullen, M., Song, E. J., Ky Hamilton, B., Moslehi, J., Armenian, S. H., Wu, J. C., Rhee, J.-W., & Ky, B. (2022) · Circulation Research · doi:10.1161/circresaha.121.319901 · Cited by 86
Androgens and the Regulation of Adiposity and Body Fat Distribution in Humans
Tchernof, A., Brochu, D., Maltais‐Payette, I., Mansour, M. F., Marchand, G. B., Carreau, A., & Kapeluto, J. (2018) · Comprehensive physiology · doi:10.1002/cphy.c170009 · Cited by 113
Bhasin, S., Lincoff, A. M., Basaria, S. S., Bauer, D. C., Boden, W. E., Cunningham, G. R., Davey, D. A., Dubcenco, E., Fukumoto, S., Garcia, M., et al. (2021) · American Heart Journal · doi:10.1016/j.ahj.2021.11.016 · Cited by 88
Testosterone Replacement Therapy and Risk of Favorable and Aggressive Prostate Cancer
Loeb, S., Folkvaljon, Y., Damber, J., Alukal, J. P., Lambe, M. P., & Stattin, P. E. (2017) · Journal of Clinical Oncology · doi:10.1200/jco.2016.69.5304 · Cited by 84
Kohn, T. P., Mata, D. A., Ramasamy, R., & Lipshultz, L. I. (2016) · European Urology · doi:10.1016/j.eururo.2016.01.043 · Cited by 88
The Endocrinology of Ageing: A Mini-Review
Jones, C. M., & Boelaert, K. (2014) · Gerontology · doi:10.1159/000367692 · Cited by 83
Sex‐specific and hormone‐related differences in vascular remodelling in atherosclerosis
Yerly, A., van der Vorst, E. P. C., Baumgärtner, I., Bernhard, S., Schindewolf, M., & Döring, Y. (2022) · European Journal of Clinical Investigation · doi:10.1111/eci.13885 · Cited by 86
Testosterone therapy, thrombosis, thrombophilia, cardiovascular events
Glueck, C. J., & Wang, P. (2014) · Metabolism · doi:10.1016/j.metabol.2014.05.005 · Cited by 79
“Finkle et al [25] conducted a cohort study of the risk of acute non-fatal myocardial infarction (MI) 90 days after an initial TT prescription in a large health-care database (n=55,593) .”
BackgroundMethodResultInfluentialMuraleedharan, V., & Jones, T. H. (2014) · Clinical Endocrinology · doi:10.1111/cen.12503 · Cited by 78
Injectable testosterone undecanoate for the treatment of hypogonadism
Corona, G., Maseroli, E., & Maggi, M. (2014) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2014.944896 · Cited by 79
“After publication of the TOM trial, two retrospective analyses have further emphasized the possible CV risk associated with T administration [103,104].”
MethodRao, P., Boulet, S. L., Mehta, A., Hotaling, J. M., Eisenberg, M. L., Honig, S. C., Warner, L., Kissin, D. M., Nangia, A. K., & Ross, L. S. (2016) · The Journal of Urology · doi:10.1016/j.juro.2016.10.063 · Cited by 77
Erythrocytosis and Polycythemia Secondary to Testosterone Replacement Therapy in the Aging Male
Jones, S. D., Dukovac, T., Sangkum, P., Yafi, F. A., & Hellstrom, W. J. G. (2015) · Sexual Medicine Reviews · doi:10.1002/smrj.43 · Cited by 76
Testosterone Therapy: What We Have Learned From Trials
Corona, G., Torres, L. O., & Maggi, M. (2020) · The Journal of Sexual Medicine · doi:10.1016/j.jsxm.2019.11.270 · Cited by 78
“In particular, they showed that TRT was associated with a 2-fold increased risk of heart attack among men aged 65 years and older, which was particularly evident in younger men with a preexisting history of heart disease.(67) Both studies present important limitations.”
BackgroundSrinath, R., Golden, S. H., Carson, K. A., & Dobs, A. S. (2015) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-3934 · Cited by 74
“In contrast, retrospective pharmaco-epidemiologic studies of T replacement have raised controversy by suggesting possible increased mortality in those treated with T compared to those not treated, particularly within the first 90 days of filling the prescription, in the elderly and in younger men with prior CHD (7, 8).”
ResultThe practical management of testosterone deficiency in men
Aversa, A., & Morgentaler, A. (2015) · Nature Reviews Urology · doi:10.1038/nrurol.2015.238 · Cited by 75
Uncovering sex-specific mechanisms of action of testosterone and redox balance
Cruz‐Topete, D., Dominic, P. S., & Stokes, K. Y. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101490 · Cited by 77
Translational Perspective on the Role of Testosterone in Sexual Function and Dysfunction
Podlasek, C. A., Mulhall, J. P., Davies, K. P., Wingard, C. J., Hannan, J. L., Bivalacqua, T. J., Musicki, B., Khera, M., González-Cadavid, N. F., & Burnett, A. L. “. (2016) · The Journal of Sexual Medicine · doi:10.1016/j.jsxm.2016.06.004 · Cited by 74
“Much of the concern pertains to potential cardiovascular morbidity and mortality arising from this therapy, stoked in part by recent publications investigating this possibility.(13,14) Longstanding reservations regarding other potential risks of therapy relating to prostate cancer, worsening lower urinary tract sympto…”
Santoro, N. F., Braunstein, G. D., Butts, C. L., Martin, K. A., McDermott, M., & Pinkerton, J. V. (2016) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2016-1271 · Cited by 75
“Recently, 2 retrospective cohort studies using large healthcare databases found an association between testosterone use and cardiovascular adverse events (115, 116).”
BackgroundGoodman, N. F., Guay, A. T., Dandona, P., Dhindsa, S., Faiman, C., & Cunningham, G. R. (2015) · Endocrine Practice · doi:10.4158/ep14434.ps · Cited by 72
Effect of lifestyle intervention on the hormonal profile of frail, obese older men
Armamento-Villareal, R., Aguirre, L. E., Qualls, C., & Villareal, D. T. (2016) · The Journal of nutrition, health and aging · doi:10.1007/s12603-016-0698-x · Cited by 67
“Given the emerging concerns on the safety of testosterone replacement raised by recent publications (35, 36), and the theoretical possibility of increased conversion of exogenous testosterone to estrogen in the large adipose tissue volume in obese subjects, other treatment modalities may also need some consideration e…”
BackgroundSchooling, C. M., Luo, S., Yeung, S. L. A., Thompson, D. J., Karthikeyan, S., Bolton, T. R., Mason, A. M., Ingelsson, E., & Burgess, S. (2018) · International Journal of Cardiology · doi:10.1016/j.ijcard.2018.05.051 · Cited by 66
“A study comparing the same individuals pre- and post-testosterone therapy to avoid these biases found a higher risk of non-fatal myocardial infarction with testosterone supplementation [6].”
BackgroundGianatti, E. J., Dupuis, P., Hoermann, R., Zajac, J. D., & Grossmann, M. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1872 · Cited by 67
“97 UKPDS 10-y CV risk, % 20 [16, 29] 22 [17, 27] .”
Metadata
- Authors
- Finkle, W. D., Greenland, S., Ridgeway, G. K., Adams, J. L., Frasco, M. A., Cook, M. B., Fraumeni, J. F., & Hoover, R. N.
- Affiliations
- University of California, Los Angeles (US)
- National Cancer Institute (US)
- Corresponding author
- Finkle, William D.
- Hoover, Robert N.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-01-29
- Volume
- 9
- Issue
- 1
- Pages
- e85805
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3905977
- OpenAlex
- W2156204904
- Cited by
- 735
- References
- 31
- Citations by year
- 2026: 21 · 2025: 34 · 2024: 33 · 2023: 42 · 2022: 45 · 2021: 32 · 2020: 41 · 2019: 52 · 2018: 69 · 2017: 87 · 2016: 79 · 2015: 112 · 2014: 86
- FWCI
- 97.58
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, public-domain)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Acute Myocardial Infarction Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Menopause: Health Impacts and Treatments
- Keywords
- testosterone replacement therapy, myocardial infarction, cardiovascular risk, phosphodiesterase-5 inhibitors, sildenafil, tadalafil, men, older men, heart disease history, drug safety, adverse drug reactions
- MeSH terms
- Tadalafil, Sildenafil Citrate, Age Factors, Aged, Carbolines, Humans, Male, Middle Aged, Myocardial Infarction, Piperazines, Purines, Risk, Sulfones, Testosterone, Prescription Drugs, Phosphodiesterase 5 Inhibitors
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