Adverse CV Events and Mortality During Testosterone Treatment

Jun 15, 2022
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Authors:
Hudson J, Cruickshank M, Quinton R, et al.
Citation:
Adverse Cardiovascular Events and Mortality in Men During Testosterone Treatment: An Individual Patient and Aggregate Data Meta-Analysis. Lancet Healthy Longev 2022;3: e381-e393.
Summary By:
Melvyn Rubenfire, MD, FACC

Quick Takes

  • Meta-analysis is not very helpful to assess treatments intended to help quality of life, of which testosterone is a good example. Placebo-controlled studies are generally not large nor long enough to draw conclusions.
  • Short- and medium-term use of testosterone appears to be safe for men with hypogonadism. However, the majority of men use testosterone for erectile dysfunction presumably for decades if effective. There are no long-term safety data from placebo-controlled studies designed to assess efficacies and risk of use of testosterone in men with and without known cardiovascular disease.
  • One of the largest and most important studies to address safety of testosterone was an observational study conducted by the Veterans Administration in men with testosterone levels <300 ng/dL who had undergone coronary arteriography: 20% began testosterone a median of 531 days following the coronary study. The absolute rate of events (fatal and nonfatal MI and strokes) were 19.9% in the no testosterone therapy group vs. 25.7% in the testosterone therapy group, with an absolute risk difference of 5.8% at 3 years after coronary angiography. In Cox proportional hazards models adjusting for the presence of coronary artery disease, testosterone use as a time-varying covariate was associated with an increased risk of adverse outcomes (hazard ratio, 1.29; 95% CI, 1.04-1.58). There was no significant difference in the effect size of testosterone therapy among those with and without coronary artery disease (test for interaction, p = 0.41) (JAMA 2013;310:1829-36).

Study Questions:

What is the effect of testosterone treatment on cardiovascular (CV) and cerebrovascular events and mortality with data derived from published studies using aggregate data and those with extensive individual participant datasets (IPD)?

Methods:

The authors conducted a systematic review and meta-analysis of randomized controlled trials including IPD from studies published in 1992 onwards (date of search, August 27, 2018). Inclusion criteria were: 1) men aged ≥18 years with a screening testosterone concentration of ≤12 nmol/L (350 ng/dL); 2) the intervention of interest was treatment with any testosterone formulation, dose frequency, and route of administration, for a minimum duration of 3 months; 3) a comparator of placebo treatment; and 4) studies assessing the prespecified primary or secondary outcomes of interest. When necessary, anonymized IPD was requested from investigators of all identified trials. Primary outcomes were mortality, and CV and cerebrovascular events at any time during follow-up. One-stage meta-analysis was used for IPD, and a two-stage meta-analysis integrating IPD with data from studies not providing IPD.

Results:

A total of 35 primary studies (5,601 participants, mean age 65 years [standard deviation 11]) from 109 peer-reviewed publications were deemed suitable. Of these, 17 studies provided IPD (3,431 participants, mean duration 9.5 months) from nine different countries, while 18 did not provide IPD data. Nearly 90% were White and nonsmokers, 27% were diabetic, and 8.4% had a previous myocardial infarction (MI). Fewer deaths occurred with testosterone treatment (6 [0.4%] of 1,621) than from placebo (12 [0.8%] of 1,537) without significant differences between groups (odds ratio [OR], 0.46; 95% confidence interval [CI], 0.17–1.24). CV risk was similar during testosterone treatment (120 [7.5%] of 1,601 events) and placebo treatment (110 [7.2%] of 1,519 events; OR, 1.07; 95% CI, 0.81–1.42). Frequently occurring CV events included arrhythmia (52 of 166 vs. 47 of 176), coronary heart disease (33 of 166 vs. 33 of 176), heart failure (22 of 166 vs. 28 of 176), and MI (10 of 166 vs. 16 of 176). Overall, patient age, baseline testosterone level, smoking status, or diabetes status were not associated with CV risk.

Conclusions:

The authors found no evidence that testosterone increased short-term to medium-term CV risks in men with hypogonadism, but there is a paucity of data evaluating its long-term safety. Long-term data are needed to fully evaluate the safety of testosterone.

Perspective:

As with many treatments with potential value for large numbers of subjects, meta-analysis does little to help the clinician decide the risk/benefit of testosterone for the majority for whom it may be prescribed. Testosterone is most often given to middle-aged men with erectile dysfunction, which may require up to 6 months for effect. The longest placebo-controlled trials are about 1 year. Fortunately, a long-term study of the safety of testosterone mandated by the FDA is ongoing.

Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Interventions and Imaging, Angiography, Nuclear Imaging, Smoking

Keywords: Arrhythmias, Cardiac, Cardiovascular Diseases, Coronary Angiography, Coronary Disease, Diabetes Mellitus, Erectile Dysfunction, Heart Disease Risk Factors, Heart Failure, Hypogonadism, Myocardial Infarction, Non-Smokers, Primary Prevention, Risk Factors, Smoking, Testosterone


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