Abstract
Purpose
We assessed the risk of ischemic stroke, transient ischemic attack, and myocardial
infarction associated with testosterone replacement therapy (TRT) among aging men
with low testosterone levels.
Methods
Using the UK Clinical Practice Research Datalink, we formed a cohort of men aged 45
years or older with low testosterone levels and no evidence of hypogonadotropic or
testicular disease, between 1995 and 2017. Hazard ratios (HRs) and 95% confidence
intervals (CIs) of a composite of ischemic stroke/transient ischemic attack and myocardial
infarction were estimated using time-dependent Cox proportional hazards models, comparing
current use of TRT with nonuse.
Results
The cohort included 15,401 men. During 71,541 person-years of follow-up, 850 patients
experienced an ischemic stroke/transient ischemic attack/myocardial infarction (crude
incidence rate 1.19 [95% confidence interval (CI), 1.11-1.27] per 100 persons per
year). Compared with nonuse, current use of TRT was associated with an increased risk
of the composite outcome (HR 1.21; 95% CI, 1.00-1.46). This risk was highest in the
first 6 months to 2 years of continuous TRT use (HR 1.35; 95% CI, 1.01-1.79), as well
as among men aged 45-59 years (HR 1.44; 95% CI, 1.07-1.92).
Conclusions
TRT may increase the risk of cardiovascular events in aging men with low testosterone
levels, particularly in the first 2 years of use. In the absence of identifiable causes
of hypogonadism, TRT should be initiated with caution among aging men with low testosterone
levels.
Keywords
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References
- Effects of testosterone replacement in hypogonadal men.J Clin Endocrinol Metab. 2000; 85: 2670-2677
- Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011.J Clin Endocrinol Metab. 2014; 99: 835-842
- Trends in androgen prescribing in the United States, 2001 to 2011.JAMA Intern Med. 2013; 173: 1465-1466
- A UK epidemic of testosterone prescribing, 2001-2010.Clin Endocrinol. 2013; 79: 564-570
- Effects of testosterone treatment in older men.N Engl J Med. 2016; 374: 611-624
- Drug Safety Communication: FDA cautions about using testosterone products for low testosterone due to aging; requires labeling change to inform of possible increased risk of heart attack and stroke with use.(Available at:)https://www.fda.gov/Drugs/DrugSafety/ucm436259.htm?attorney_name=Brett%20Hollett?PageSpeed=noscriptDate: 2015Date accessed: April 7, 2019
- No consistent evidence of an increased risk of heart problems with testosterone medicines.(Available at:)https://www.ema.europa.eu/en/news/no-consistent-evidence-increased-risk-heart-problems-testosterone-medicinesDate: 2014Date accessed: April 7, 2019
- Association between exogenous testosterone and cardiovascular events: an overview of systematic reviews.Lancet Diabetes Endocrinol. 2016; 4: 943-956
- Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.JAMA. 2013; 310: 1829-1836
- Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.PLoS One. 2014; 9e85805
- Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency.JAMA Intern Med. 2017; 177: 491-499
- Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men.Eur Heart J. 2015; 36: 2706-2715
- Summary safety review - testosterone replacement products - cardiovascular risk.(Available at:)https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?linkID=SSR00058Date: 2014Date accessed: April 7, 2019
- Evaluation and treatment of male hypogonadism.JAMA. 2018; 319: 1375-1376
- Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744
- Use of the UK General Practice Research Database for pharmacoepidemiology.Br J Clin Pharmacol. 1998; 45: 419-425
- The General Practice Research Database.Drug Saf. 2004; 27: 871-881
- Data resource profile: Clinical Practice Research Datalink (CPRD).Int J Epidemiol. 2015; 44: 827-836
- The Read clinical classification.BMJ. 1990; 300: 1092
- Dictionary of medicines and devices (dm+d).(Available at:)https://www.nhsbsa.nhs.uk/pharmacies-gp-practices-and-appliance-contractors/dictionary-medicines-and-devices-dmdDate accessed: April 7, 2019
- Validity of the general practice research database.Pharmacotherapy. 2003; 23: 686-689
- Validity of diagnostic coding within the General Practice Research Database: a systematic review.Br J Gen Pract. 2010; 60: e128-e136
- Completeness and diagnostic validity of recording acute myocardial infarction events in primary care, hospital care, disease registry, and national mortality records: cohort study.BMJ. 2013; 346: f2350
- The quality of information recorded on a UK database of primary care records: a study of hospitalizations due to hypoglycemia and other conditions.Pharmacoepidemiol Drug Saf. 1994; 3: 15-21
- Marginal structural models and causal inference in epidemiology.Epidemiology. 2000; 11: 550-560
- Adverse events associated with testosterone administration.N Engl J Med. 2010; 363: 109-122
- Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials.J Gerontol A Biol Sci Med Sci. 2005; 60: 1451-1457
- Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials.Mayo Clin Proc. 2007; 82: 29-39
- Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis.J Clin Endocrinol Metab. 2010; 95: 2560-2575
- Testosterone prescribing in the united states, 2002-2016.JAMA. 2018; 320: 200-202
- Testosterone replacement therapy and the risk of stroke in men: a systematic review.Maturitas. 2017; 106: 31-37
- Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME).Int J Clin Pract. 2016; 70: 843-852
- Testosterone therapy and risk of myocardial infarction: a pharmacoepidemiologic study.Pharmacotherapy. 2015; 35: 72-78
- Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study.Lancet Diabetes Endocrinol. 2016; 4: 498-506
- Bias from depletion of susceptibles: the example of hormone replacement therapy and the risk of venous thromboembolism.Pharmacoepidemiol Drug Saf. 2017; 26: 554-560
- Testosterone treatment and risk of venous thromboembolism: population based case-control study.BMJ. 2016; 355i5968
- Testosterone therapy, association with age, initiation and mode of therapy with cardiovascular events: a systematic review.Clin Endocrinol. 2016; 85: 436-443
- Testosterone and atherosclerosis.Growth Hormon IGF Res. 2003; 13: S72-S84
- Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses.Circulation. 1995; 91: 2742-2747
- Atherosclerosis, platelets and thrombosis in acute ischaemic heart disease.Eur Heart J Acute Cardiovasc Care. 2012; 1: 60-74
- Testosterone treatment and coronary artery plaque volume in older men with low testosterone.JAMA. 2017; 317: 708-716
- Polycythemia as a complication of testosterone replacement therapy in nursing home men with low testosterone levels.J Am Geriatr Soc. 1995; 43: 899-901
- Erythrocytosis and polycythemia secondary to testosterone replacement therapy in the aging male.Sex Med Rev. 2015; 3: 101-112
- Cardiovascular events and intensity of treatment in polycythemia vera.N Engl J Med. 2013; 368: 22-33
- Obstructive sleep apnea and cardiovascular disease.J Am Coll Cardiol. 2003; 41: 1429-1437
- The short-term effects of high-dose testosterone on sleep, breathing, and function in older men.J Clin Endocrinol Metab. 2003; 88: 3605-3613
- Testosterone treatment and mortality in men with low testosterone levels.J Clin Endocrinol Metab. 2012; 97: 2050-2058
- Testosterone therapy in men with hypogonadism: an Endocrine Society Clinical Practice Guideline.J Clin Endocrinol Metab. 2018; 103: 1715-1744
Article info
Publication history
Published online: April 03, 2019
Footnotes
Funding: This study is supported, in part, by funding from the Canadian Institutes of Health Research.
Conflict of Interest: None declared.
Authorship: All authors had access to the data and a role in writing the manuscript.
Identification
Copyright
© 2019 Elsevier Inc. All rights reserved.
