Dr. Ron’s Research Review – March 6, 2014

© 2014

This week’s research review focuses on an analysis of Finkle 2014 on testosterone.

"Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men." was recently published in PLoS One. (Finkle, Greenland et al. 2014)

The authors state: "No data were available on indications for TT prescription, race, laboratory findings, occupational, environmental, or lifestyle factors."

They used the MarketScan Commercial Claims and Encounters Database, which is useful for "understanding the total health cost of a particular medication" and "assessing cost-effectiveness". (Adamson, Chang et al. 2008)

There are two other MarketScan databases that provide detailed relevant information for this type of study.

The Marketscan health risk assessment Database includes Height, Weight, Total cholesterol, Glucose, Blood pressure, Body Mass Index (BMI), HDL and LDL, etc.

MarketScan Lab includes inpatient, outpatient, drug, enrollment, and lab test results, etc.

The study uses statistical weighting: "Doubly robust estimation in missing data and causal inference models."

"Although sophisticated statistical analysis has a vital role in biomedical research, it should be understood that the reliability of a result decreases the further it is removed from the raw data. (Morgentaler and Kacker 2014)

The main issues are form and aromatization. Of the patients receiving testosterone therapy, prescriptions were as follows.




1% 5-g




200 mg/mL





The authors state: "There was a relatively small group of patients with extended follow-up time (267 patients at 2000 days after coronary angiography) so that our estimates of the risk of testosterone therapy are less reliable."

Table 2 compares the two groups. For almost every column, the testosterone group has more health issues and is on more medications! Notably: Osteoarthritis, Asthma, Vasodilators, SSRIs, Insulin and Anti-diabetes drugs.

This key sentence indicates a study selection bias: "PDE5I is recommended for men healthy enough to engage in sexual activity." A more appropriate comparison would be between PDE5 inhibitors and testosterone prescribed specifically for erectile dysfunction.

Although one study shows the diagnosis code for an MI is accurate, the same cannot be said for the diagnostic covariates associated with an MI. The study is based on ICD9 insurance codes, which assumes that a physician fills out all relevant codes at every visit.

This study was a comparison between prescriptions for PDE5 inhibitor drugs and testosterone. No comparison was made between those not taking either medication (e.g. a matched control group).

Dr. Ron


Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men

         (Finkle, Greenland et al. 2014) Download

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 (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). 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.


Adamson, D. M., S. Chang, et al. (2008) "Health Research Data for the Real World: The MarketScan Databases. White paper."

Finkle, W. D., S. Greenland, et al. (2014). "Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men." PLoS One 9(1): e85805. [PMID: 24489673]

Morgentaler, A. and R. Kacker (2014). "Andrology: Testosterone and cardiovascular risk-deciphering the statistics." Nat Rev Urol. [PMID: 24535586]