Authors Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, et al
Review Date February 2014
Citation PLoS ONE 9(1): e85805. doi:10.1371 (January 2014)
Dramatic increases in the use of testosterone therapy (TT) in both older and younger men have been reported recently. There have also been several recent studies suggesting an association between TT and cardiovascular disease including a clinical trial in old frail men that was stopped due to adverse cardiovascular events, and an observational study of men in a Veteran’s healthcare system in the USA that showed as association between TT a combined outcome measure of overall mortality, MI and stroke.
The authors used a large healthcare database in the USA to investigate the question of whether TT increases the risk of acute non-fatal myocardial infarction (MI), and whether any effect might be stronger in those with pre-existing cardiac disease. The study also investigate the associations in younger as well as older men.
55,593 men in a large health-care database were included in the cohort with data from 2006 – 2010. The outcome of acute non-fatal MI was assessed following an initial TT prescription. The incidence rate of MI in the 90 days following the initial prescription (post-prescription interval) was compared with the rate in the one year prior to the initial prescription (pre-prescription interval) (post/pre). A comparison group of 167,279 men prescribed phosphodiesterase type 5 inhibitors (PDE5i; sildenafil or tadalafil) was assessed in a similar manner. TT prescription post/pre rates were also compared with the PDE5I post/pre rates, adjusting for potential confounders using doubly robust estimation. Men with a history of MI prior to the first prescription of TT or PDE5i were excluded from the analysis. A large number of covariates were considered including co-morbidities, prescription medications and age.
In all subjects, the TT post/pre-prescription rate ratio (RR) for MI was 1.36 (95% CI: 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 (ptrend = 0.03), while no trend was seen for PDE5i (ptrend = 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).
This study demonstrated an increased risk of MI following initiation of TT prescription in older men (≥ 65 years old), and in younger men (< 65 years) with pre-existing diagnosed heart disease. Given the recent trends in T prescribing these data, in addition to other recent studies, underline the need for adequately powered clinical trials to fully assess the benefits and risks of TT.
Points to Note
- This large epidemiological study demonstrated an association between testosterone therapy and MI in the 90 days following the filling of a prescription for testosterone in older men and, contrary to previous studies of predominantly older men, demonstrated a risk specifically in younger men with pre-existing heart disease.
- These findings add support to the concerns about cardiovascular risk at a time of increasing testosterone prescribing in both older and younger men.
- The limitations of this database study included: a lack of information on indications for treatment or serum testosterone levels; only non-fatal MI was considered; MI diagnosis from the attending physician only; unmeasured confounding; CV events apart from MI were not assessed.
- There are several plausible biological mechanisms through which TT might increase cardiovascular risk and it appears that exogenous and endogenous testosterone may have differing effects.
- Further research is needed to examine wider range of CV outcomes, to assess dose and indication for TT, and associations at varying levels of serum testosterone and hypogonadism.
- Appropriately powered clinical trials are needed to assess benefits and risk of TT and given the increasing prescribing trends there is some urgency for trial results.