Data fail to support concerns over T therapy, CV risk

Dr. Morgentaler is director of Men’s Health Boston and an associate clinical professor of urology at Harvard Medical School, Beth Israel Deaconess Medical Center, Boston.

By now, most urologists and many of our patients are aware of concerns regarding cardiovascular (CV) risks associated with testosterone (T) therapy. This concern arose out of the blue in November 2013 with publication of a study in JAMA by Vigen et al (JAMA 2013; 310:1829-36) that reported increased CV risks in men who received a T prescription, and this result appeared to be confirmed by publication of another study in January 2014 in PLoS One by Finkle et al (PloS One 2014; 9:e85805). The widespread media attention given to these two studies prompted the FDA to announce a planned review of CV risks with T products, and precipitated a brand-new area of medical malpractice, as plaintiff attorneys now advertise nationwide for cases of myocardial infarction (MI) or stroke after use of T therapy (J Mens Health 2014; 11:1-3).

Related - Decision to use testosterone must be individualized

A multidisciplinary group of T experts in urology and other fields (endocrinology, family practice, steroid biochemistry) strongly believes the evidence on this issue has been distorted and fails to indicate CV risk, and has formed the Androgen Study Group (ASG) to promote accurate reporting of testosterone research.

For several decades, there had been accumulating evidence associating higher serum T concentrations with reduced risk of atherosclerosis and mortality, and clear evidence that T therapy reduced well-known CV risk factors, such as obesity, fat mass, insulin resistance, and glycemic control (Am J Medicine 2011; 124:578-87). So it was surprising to many in the field when Vigen et al reported increased rates of myocardial infarction, stroke, and death in men who received a T prescription compared with untreated men (JAMA 2013; 310:1829-36). The study analyzed data for 8,709 VA patients with serum T <300 ng/dL who had undergone coronary angiography. The authors reported that at 3 years following angiography, the absolute rate of adverse events (myocardial infarction, stroke, and death) in the T group was 25.7% compared with 19.9% in the untreated group.

Next: Numbers were incorrect

More on testosterone

New study: No increased risk of MI with testosterone

Positive data on T products follow blood clot warning

FDA approves another testosterone replacement gel

Numbers were incorrect

These numbers were widely reported in media stories, but were incorrect. Absolute rates of events were only 10.1% (123 events in 1,223 men) for the T group and 21.2% (1,587 events in 7,486 men) in the untreated group (JAMA 2014; 311:961-2). The authors reversed these results that indicated a benefit in those who received T using a new and unvalidated statistical methodology (stabilized inverse propensity weighting applied to Kaplan-Meier curves) that involved adjustment for more than 50 variables, and misreported their results as absolute risk, a term that implies results were based on actual events (Nat Rev Urol 2014; 11:131-2; J Urol Apr 16, 2014 [Epub ahead of print]).

I apprised the editor-in-chief of JAMA, Howard Bauchner, MD, of this error via telephone call, and 3 days later JAMA published a revised version that replaced “absolute rate of events” with “Kaplan-Meier estimated cumulative percentages with events,” the latter terminology appropriately reflecting the highly statistical nature of the analysis.

The study by Finkle et al was even weaker. The authors reported that rates of non-fatal MI in 55,593 men were higher in the period up to 90 days after receiving a T prescription than in the prior 12 months. However, these two comparison periods are unrelated (J Sex Med 2014; 11:1362-6). Although the post-prescription MI rate may reasonably reflect MI rates in this population, as a retrospective study, the MI rate in the prior 12 months reflects only the willingness of health care providers to prescribe T therapy to men with a history of recent MI. Any reluctance to prescribe T to such men will result in a reduced “MI rate,” which in turn will lead to a false conclusion that MI rates were increased post prescription, even if those rates were low.

In fact, the reported post-prescription MI rate of 4.75 events per 1,000 person-years was very low, at approximately one-third the expected rate based on the National Heart, Lung, and Blood Institute’s “CVD Risk Calculator” (http://cvdrisk.nhlbi.nih.gov/calculator.asp).

Androgen Study Group urges retraction

The argument that T therapy was associated with increased CV risk was further undermined when a second correction to the study by Vigen et al was published in March 2014, revealing a series of data errors involving more than 1,000 men in one group, more than 900 in a second group, and the revelation that 9% of the all-male dataset was comprised of women (JAMA 2014; 2311:2967).

In response, the ASG drafted a letter urging JAMA to retract the article due to “data mismanagement and contamination” that rendered the study “no longer credible.” Within 10 days, the letter had been co-signed by more than 160 leading figures in the field from 32 countries, including more than 60 full professors, eight emeritus professors, and nine journal editors. Two weeks later, the call for retraction was joined by 29 medical societies, including two specialty societies of the AUA: the Sexual Medicine Society of North America and the American Society for Men’s Health (Aging Male 2014; 17:63-5). This action represents a global repudiation of this study as credible evidence of increased CV risk with T therapy. JAMA has so far declined to retract the article.

Next: FDA rejects petition

In response to a petition to the FDA submitted by Public Citizen urging the addition of a black box warning and other restrictions on T products, and separately with regard to the FDA’s upcoming review of CV risk with T products, the ASG submitted its own analysis of the studies by Vigen et al and Finkle et al, together with one of the most comprehensive compilations of studies regarding T and CV risk (available on the ASG website, www.androgenstudygroup.org). When one tallies the numbers of studies showing a beneficial or deleterious effect of higher T-endogenous or via T therapy-for the issues of mortality, incident coronary artery disease, severity of coronary artery disease, carotid intima-media thickness, and changes in CV risk factors such as fat mass, the “score” is 46 to 0 in favor of beneficial effects (www.androgenstudygroup.org/initiatives/letter-to-fda-asking-to-deny-black-box-petition).

On July 16, 2014, the FDA declined Public Citizen’s petition, agreeing that neither the study by Vigen et al nor the study by Finkle et al provided compelling evidence of increased CV risk.

Science is messy, and it is understood that every now and then a study will be published that appears to run counter to existing evidence. However, it is critical to understand that not all studies are equal in value and that journals unfortunately have a bias toward publishing studies likely to generate interest and controversy. The consumer media, in turn, appears to value studies suggesting risk over studies that provide reassuring results.

A case in point is the recently published study by Baillargeon and colleagues (Ann Pharmacother Jul 2, 2014 [Epub ahead of print]) that examined a large Medicare database and reported that T prescriptions were not associated with increased risk of MI overall, and that T therapy was actually associated with reduced events for men in the highest prognostic risk quartile. This well-done study by a respected research group using established statistical methods received minimal media coverage.

All treatments entail some risk, including T therapy. Those risks include erythrocytosis, acne, pedal edema, and gynecomastia. At this point, there are no compelling data to support the notion that T therapy is associated with CV risks, and there is suggestive evidence it may even be helpful.UT

Disclosures: Dr. Morgentaler has served as a scientific study investigator for Eli Lilly, Auxilium Pharmaceuticals, Sophiris Bio, Lipocine, Antares Pharma, and Warner Chilcott; a meeting participant/lecturer for Merck; scientific advisory board member for AbbVie, Auxilium, and Clarus Therapeutics; and a consultant for Auxilium. He is chairman of the Androgen Study Group (ASG), which receives no funding from any pharmaceutical company.  Other members of the ASG are Andre Guay, MD (endocrinology), Mohit Khera, MD, MPH (urology), Martin Miner, MD (family practice), and Abdul Traish, PhD (basic science research).

Subscribe to Urology Times to get monthly news from the leading news source for urologists.