Practice Update: Cardiology

ARRHYTHMIAS/HEART RHYTHM DISORDERS 15

Incidence of AF sinks following normalization of testosterone levels after testosterone replacement therapy Journal of the American Heart Association Take-home message

ratio 0.79, 95%CI 0.70-0.89, P=0.0001). There was no statistical difference between groups 2 and 3 (hazard ratio 0.89, 95%CI 0.78- 1.0009, P=0.0675) in incidence of AF. CONCLUSIONS These novel results suggest that normalization of TT levels after TRT is associated Discrepant findings in studies of cardi- ovascular outcomes in men receiving testosterone therapy likely reflect biases inherent to retrospective studies. Selection of patients for testosterone measurement COMMENT By James P Walsh MD, PhD T estosterone replacement is widely prescribed to older men with func- tional declines in testosterone, but its effects on cardiovascular disease are controversial. Some observational studies have reported associations of testosterone therapy with improved outcomes, while others suggest increased cardiovascular events. Sharma et al have now examined the relationship between testosterone ther- apy and new-onset atrial fibrillation in male veterans with a documented testosterone level below the reference range prior to testosterone therapy. 1 This group previ- ously reported associations of testosterone therapy with reductions inmortality, MI, and stroke in this same veteran cohort. 2 Participants were divided into three groups. Group 1 included 40,856 tes- tosterone-treated veterans with normalization of testosterone on ther- apy; group 2 included 23,930 treated veterans whose testosterone did not normalize; and group 3 included 11,853 veterans not treated who continued to have low testosterone. Data were ana- lyzed using a Cox proportional hazard model propensity weighted for multiple comorbid conditions, demographics, and concurrent medications. Men who had testosterone therapy with normalization of testosterone (group 1) had a lower risk of atrial fibrillation in comparison with group 2 (HR, 0.90; 95% CI, 0.81–0.99; P = 0.0255) and group 3 (HR, 0.79; CI, 0.70– 0.89; P = 0.0001). There was no significant difference between groups 2 and 3.

• This study used data from 76,639 veterans with low levels of serum total testosterone to explore the effect of testosterone normalization on new incidence of atrial fibril- lation (AF) following testosterone replacement therapy (TRT). Of these patients, 40,856 had TRT resulting in normalized testosterone levels (group 1), 23,939 patients had TRT that did not result in normalized testosterone levels (group 2), and 11,853 patients did not receive TRT (group 3). A significantly lower risk of AF was reported in group 1 compared with group 2 and group 3. No differ- ences in AF incidence were reported between group 2 and group 3. • Normalization of total testosterone levels following TRT may be asso- ciated with significantly decreased AF incidence. Abstract BACKGROUND Atrial fibrillation (AF) is the most common cardiac dysrhythmia associated with significant morbidity and mortality. Several small studies have reported that low serum total tes- tosterone (TT) levels were associated with a higher incidence of AF. In contrast, it is also reported that anabolic steroid use is associated with an increase in the risk of AF. To date, no study has explored the effect of testosterone normalization on new incidence of AF after tes- tosterone replacement therapy (TRT) in patients with low testosterone. METHODS AND RESULTS Using data from the Veter- ans Administrations Corporate Data Warehouse, we identified a national cohort of 76 639 veterans with low TT levels and divided them into 3 groups. Group 1 had TRT resulting in normalization of TT levels (normalized TRT), group 2 had TRT without normalization of TT levels (nonnormalized TRT), and group 3 did not receive TRT (no TRT). Propen- sity score-weighted stabilized inverse probability of treatment weighting Cox proportional hazard methods were used for analysis of the data from these groups to determine the association between post-TRT levels of TT and the incidence of AF. Group 1 (40 856 patients, median age 66 years) had significantly lower risk of AF than group 2 (23 939 patients, median age 65 years; hazard ratio 0.90, 95%CI 0.81-0.99, P=0.0255) and group 3 (11 853 patients, median age 67 years; hazard

and therapy is one potential source of resid- ual bias. 3 Other limitations include broad overlap of testosterone levels in eugo- nadal and hypogonadal men and a lack of clinical data on the basis for diagnosis of hypogonadism in the study participants. A particular concern with this study is the exclusion of men who had a subsequent normal testosterone off therapy from the control group, as these men would pre- sumably not have been excluded had they been given testosterone. Lack of data on duration of therapy is also problematic, as many men started on testosterone discon- tinue it after a short period. Overall, this study is likely confounded by the same biases that have led to dis- cordant findings in other studies of other cardiovascular endpoints in men using testosterone. Until more definitive pro- spective data are available, a careful approach to testosterone replacement in older men with significant cardiovas- cular risk, as outlined in 2010 Endocrine Society guidelines, is recommended. 4 References 1. Sharma R, Oni OA, Gupta K, et al. J Am Heart Assoc 2017;6(5):e004880. 2. Sharma R, Oni OA, Gupta K, et al. Eur Heart J 2015; 36(40):2706-2715. 3. Kloner RA, Carson C, Dobs A, et al. J Am Coll Cardiol 2016;67(5):545-557. 4. Bhasin S, Cunningham GR, Hayes FJ, et al. J Clin Endocrinol Metab 2010;95(6):2536-2559. 

Dr Walsh is Associate Professor of Medicine, Biochemistry, and Molecular Biology at Indiana University School of Medicine, and Section Chief of Endocrinology at Roudebush VA Medical Center in Indiana.

with a significant decrease in the incidence of AF. Normalization of testosterone levels after tes- tosterone replacement therapy is associated with decreased incidence of atrial fibrillation. J Am Heart Assoc 2017 May 09;6(5)e004880, R Sharma, OA Oni, K Gupta, et al.

VOL. 2 • NO. 1 • 2017