Testosterone Therapy and Cardiovascular Risks: Study Details and Analysis

Although no significant differences in event rates were noted at any year of follow-up, a significant increase of 29% for testosterone-treated men was reported over the course of the study.

Curiously, the percentage of men who suffered an event was actually lower by one half for the testosterone group compared with the no-testosterone group (10.1% vs 21.2%). The authors came to an opposite conclusion resulting from complex statistical modeling based on more than 50 variables, including time (2). However, this modeling failed to include substantially lower baseline testosterone levels in the T group, despite evidence that lower T values are associated with increased CV risk and mortality (3,4). These statistical adjustments resulted in an estimated cumulative event rate for the testosterone group of >30% compared with the actual rate of only 10.1%. This multiplier effect for events also multiplies the magnitude of errors, raising considerable concern regarding the reliability of results.

Most importantly, the authors inexplicably excluded 1132 men who suffered stroke or heart attack prior to receiving a testosterone prescription. These men all had events during the study period and all should have been included in the no-testosterone group. This would have increased the rate of events in the no-testosterone group by 71%, likely reversing the results (2). It is impossible to conclude from this study that testosterone prescriptions increase rates of cardiovascular events.

The second study published in PLoS one by Finkle et al (5) in January, 2014, was a retrospective analysis of insurance claims data in 55,593 men in which the only information available were diagnosis codes, procedure codes, and prescription data. The primary result was an increased rate of non-fatal myocardial infarction within 90 days after filling a testosterone prescription compared with the prior 12 months. The authors also compared pre- and post-prescription rates for phosphodiesterase 5 inhibitors (PDE5i) such as Cialis and Viagra, reporting no increase in MI following PDE5i prescriptions. Subgroups by age revealed increased risk of MI with men over 65y without a prior history of heart disease, and for men less than 65y with a prior history of heart disease. The authors concluded that the risk of MI is increased in older men and in younger men with pre-existing known heart disease who received testosterone prescriptions.

This study received enormous media attention despite a number of serious shortcomings that render its conclusions highly questionable. First, the authors chose to report results only for the very short period after men filled a first T prescription. This period was determined by first prescription refill, which in theory could be up to 90 days, but for many men would be 30 days. Note that the result of an increased MI was a comparison of the same group before and after a prescription. It is impossible from this design to distinguish whether any observed difference was due to the underlying condition (T deficiency) or to its treatment (T prescription). The shorter the exposure time for a drug, the less likely it is responsible for an observed difference. It is thus notable, and troubling, that the authors provided results only for a very short follow-up period rather than for a longer period, such as 12 months, even though this information was available to them. Presumably, the authors would have reported a significant difference if it existed, raising a concern that the observed difference no longer persisted over time.

Second, the excess risk of MI with T prescriptions was remarkably low. The pre-prescription MI rate in the testosterone-treated group was 3.48 per 1000 person-years, and the post-prescription rate was 4.75 per 1000 person years. The excess non-fatal MI risk was therefore 1.27 events for every 1000 person-years. This difference is clinically meaningless, and so small as to be unlikely to be reproducible.

Third, the comparison with MI rates with PDE5i prescriptions is misleading and provides no useful information. This is a classic case of apples and oranges. These were two dissimilar groups (men undergoing treatment for T deficiency and men being treated for erectile dysfunction) that were each subjected to dissimilar treatments. Finally, there was a very low number of post-prescription events in each of the subgroups (8, 12, 15, and 30) based on age and presence or absence of heart disease. When numbers are this low, a shift of one or two events can significantly alter results. Combined with the extremely low overall risk, any conclusions regarding risks for subgroups is highly questionable.

Both of these studies are retrospective observational studies. As such they lack control groups and are thus unable to isolate a single variable to account for any observed difference, such as testosterone prescriptions. These types of observational studies are prone to bias and error, and are frequently found to be irreproducible or the magnitude of effect greatly reduced (6). For these reasons, Marcia Angell, former editor at the New England Journal of Medicine, has suggested that “we are looking for a relative risk of three or more [before accepting a paper for publication], particularly if it is biologically implausible or if it’s a brand new finding” (7). By comparison, the increased relative risk was only 0.29 for Vigen et al (1), and 0.37 for Finkle et al (5). In addition, each study suffers from significant design or methodological flaws that make results or their interpretation doubtful. The study by Vigen et al (1) could easily be interpreted to show a beneficial effect from T therapy, particularly if the excluded men who received a prescription after MI or stroke were included. The study by Finkle et al (5) more plausibly demonstrates that cardiovascular risks are associated with the condition of T deficiency.

What does the literature show regarding T and cardiovascular risk?
A wealth of evidence indicates that low levels of testosterone are associated with cardiovascular risks and known risk factors for cardiovascular disease, such as obesity, diabetes, and the metabolic syndrome (3). Nine of eleven longitudinal studies have demonstrated increased mortality rates in men with lower levels of testosterone and improved survival in those with higher testosterone. The other two showed no effect (8-18). In placebo-controlled trials men who received testosterone demonstrated increased angina-free exercise capacity (19), and improved functional capability in men with congestive heart failure (20, 21). Most relevant for comparison with the studies by Vigen et al (1) and Finkle et al (5) are two retrospective studies that demonstrated reduced mortality, by half, in men with T <300ng/dl who received testosterone prescriptions compared with men who did not (22,23).

The single prior study that raised concerns that T therapy may increase adverse cardiovascular events was a 6-month randomized trial of testosterone gel versus placebo in older men with impaired mobility, designed to test for functional improvements with treatment (24). However, this study was not designed to assess CV risk, and its report of increased adverse events in the T group compared with placebo was based on a wide variety of events of questionable significance, such as pedal edema, palpitations, and premature ventricular contractions. Only 4 major CV adverse events (one death, two MIs, one stroke) occurred over 6 months in 209 men with substantial comorbidities, all occurring in the T-group. Although this asymmetric distribution appears concerning, a similar placebo-controlled testosterone study in older, frail men reported two major CV events, both occurring in the placebo group (25). In addition, a prior meta-analysis of 19 placebo-controlled T trials noted two deaths, both in the placebo study arms (26). Given the low number of serious events and the absence of any pre-determined CV endpoints or specific CV investigations, it is difficult to conclude from this study that T therapy is associated with increased CV risk.

To date, we are unaware of any experimental study that provides compelling evidence that T therapy increases cardiovascular risk. On the contrary, a wealth of information suggests adverse cardiovascular outcomes are associated with low testosterone levels, and testosterone therapy appears to be beneficial for cardiovascular health. Additional insight into the impact of testosterone therapy on cardiovascular risk should come from the large ongoing testosterone trial of 800 men 65 years or older sponsored by the National Institutes of Health. Further randomized controlled trials are needed to provide a more definitive assessment of cardiovascular risks and benefits with T therapy.

References

  1. Vigen R, O’Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME, Plomondon ME, Rumsfeld JS, Ho PM. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310:1829-1836.
  2. Morgentaler A, Kacker R. Testosterone and cardiovascular risk—deciphering the statistics. Nat Rev Urol, epub Feb 2014
  3. Traish AM, Miner M, Zitzmann M, Morgentaler A. Testosterone deficiency. Am J Medicine, 124, 578-587, 2011.
  4. Oskui PM, French WJ, Herring MJ, Mayeda GS, Burstein S, Kloner RA. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. J Am Heart Assoc. 2013 Nov 15;2(6):e000272
  5. Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, Fraumeni Jr JF, Hoover RN. Increasing Risk of Non-Fatal Myocardial Infarction Following Testosterone Therapy Prescription in Men. PLoS ONE 9(1): e85805. Doi: 10.1371/journal.pone.0085805
  6. Ioannidis, J. P. A. Contradicted and initially stronger effects in highly cited clinical research. Journal of the American Medical Association, 2005; 294, 218–228.
  7. Taubes G, Mann CC. Epidemiology faces its limits. Science 1995, 269:164-9.
  8. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med. 2006;166:1660–1665.
  9. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008;93:68–75.
  10. Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, Welch A, Day N. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation. 2007;116:2694–2701.
  11. Haring R, Volzke H, Steveling A, Krebs A, Felix SB, Schofl C, Dorr M, Nauck M, Wallaschofski H. Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79. Eur Heart J. 2010;31:1494–1501.
  12. Malkin CJ, Pugh PJ, Morris PD, Asif S, Jones TH, Channer KS. Low serum testosterone and increased mortality in men with coronary heart disease. Heart. 2010;96:1821–1825.
  13. Tivesten A, Vandenput L, Labrie F, Karlsson MK, Ljunggren O, Mellstrom D, Ohlsson C. Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab. 2009;94:2482–2488.
  14. Menke A, Guallar E, Rohrmann S, Nelson WG, Rifai N, Kanarek N, Feinleib M, Michos ED, Dobs A, Platz EA. Sex steroid hormone concentrations and risk of death in US men. Am J Epidemiol. 2010;171:583–592.
  15. Vikan T, Schirmer H, Njolstad I, Svartberg J. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromso Study. Eur J Endocrinol. 2009;161:435–442.
  16. Corona G, Monami M, Boddi V, Cameron-Smith M, Fisher AD, de Vita G, Melani C, Balzi D, Sforza A, Forti G, Mannucci E, Maggi M. Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction. J Sex Med. 2010 Apr;7(4 Pt 1):1557-64.
  17. Hyde Z, Norman PE, Flicker L, Hankey GJ, Almeida OP, McCaul KA, Chubb SA, Yeap BB.Low free testosterone predicts mortality from cardiovascular disease but not other causes: the Health in Men Study. J Clin Endocrinol Metab. 2012 Jan;97(1):179-89.
  18. Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA.Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96:3007-3019.
  19. English KM, Steeds RP, Jones TH, Diver MJ & Channer KS. Low dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina – a randomized, double-blind, placebo-controlled study. Circulation 2000; 102: 1906–1911.
  20. Stout M, Tew GA, Doll H, Zwierska I, Woodroofe N, Channer KS, Saxton JM. Testosterone therapy during exercise rehabilitation in male patients with chronic heart failure who have low testosterone status: a double-blind randomized controlled feasibility study. Am Heart J. 2012 Dec;164(6):893-901.
  21. Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, Mammi C, Piepoli M, Fini M, Rosano GM. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol. 2009 Sep 1;54(10):919-27.
  22. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012;97:2050-2058.
  23. Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH.Testosterone deficiency is associated with increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur J Endocrinol. 2013;169:725-733.
  24. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S. Adverse events associated with testosterone administration. N Engl J Med. 2010 Jul 8;363(2):109-22.
  25. O’Connell MD, Roberts SA, Srinivas-Shankar U, Tajar A, Connolly MJ, Adams JE, Oldham JA, Wu FC. (2011). Do the effects of testosterone on muscle strength, physical function, body composition, and quality of life persist six months after treatment in intermediate-frail and frail elderly men? Journal of Clinical Endocrinology and Metabolism, 96(2), 454-458.
  26. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, Bhasin S. 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 Nov;60(11):1451-7.
Image

Members Only

Newsletter

ISSM Update