Normalization of Testosterone Level and Incidence of MI in Men
Aims There is a significant uncertainty regarding the effect of testosterone replacement therapy (TRT) on cardiovascular (CV) outcomes including myocardial infarction (MI) and stroke. The aim of this study was to examine the relationship between normalization of total testosterone (TT) after TRT and CV events as well as all-cause mortality in patients without previous history of MI and stroke.
Methods and results We retrospectively examined 83 010 male veterans with documented low TT levels. The subjects were categorized into (Gp1: TRT with resulting normalization of TT levels), (Gp2: TRT without normalization of TT levels) and (Gp3: Did not receive TRT). By utilizing propensity score-weighted Cox proportional hazard models, the association of TRT with all-cause mortality, MI, stroke, and a composite endpoint was compared between these groups. The all-cause mortality [hazard ratio (HR): 0.44, confidence interval (CI) 0.42–0.46], risk of MI (HR: 0.76, CI 0.63–0.93), and stroke (HR: 0.64, CI 0.43–0.96) were significantly lower in Gp1 (n = 43 931, median age = 66 years, mean follow-up = 6.2 years) vs. Gp3 (n = 13 378, median age = 66 years, mean follow-up = 4.7 years) in propensity-matched cohort. Similarly, the all-cause mortality (HR: 0.53, CI 0.50–0.55), risk of MI (HR: 0.82, CI 0.71–0.95), and stroke (HR: 0.70, CI 0.51–0.96) were significantly lower in Gp1 vs. Gp2 (n = 25 701, median age = 66 years, mean follow-up = 4.6 years). There was no difference in MI or stroke risk between Gp2 and Gp3.
Conclusion In this large observational cohort with extended follow-up, normalization of TT levels after TRT was associated with a significant reduction in all-cause mortality, MI, and stroke.
Professional guidelines recommend testosterone replacement therapy (TRT) in patients with signs and symptoms of hypogonadism and documented evidence of low testosterone (T) levels. The diagnosis of late-onset hypogonadism is on the rise with estimates that nearly 2.4 million men aged 40–69 suffer from hypogonadism in the USA. Even though late-onset hypogonadism is not a universally accepted concept, and FDA has advised against T supplementation in men on the basis of age alone. However, in the last decade there has been a nearly 400% increase in the number of TRT prescriptions creating a billion dollar market. With such widespread and ever increasing use of TRT, there has been growing concern regarding its effect on mortality and cardiovascular (CV) outcomes.
Recent retrospective studies, multiple meta-analyses, and a few small prospective studies have presented conflicting results and contributed to this uncertainty. Observational studies suggested that low serum T level is associated with increased CV events. Clinical trials examining TRT have been relatively small, and these trials were underpowered to provide conclusive evidence related to CV events. For instance, a small prospective study in frail elderly men showed an increased incidence of CV events with TRT and was stopped early. Two separate retrospective studies of men in the Veterans Affairs (VA) Health System using two different databases reported opposite effects of TRT on all-cause mortality. In two very recent studies, Vigen et al. using a VA database and Finkle et al. using a healthcare database reported that men receiving TRT had an increased risk of myocardial infarction (MI). It is important to note that in many of these studies repeat measurements to document normalization of T levels after TRT were lacking. On the heels of these recently published data, the FDA issued a drug safety alert related to TRT (http://www.fda.gov/Drugs/DrugSafety/ucm383904.htm).
In light of these conflicting results and uncertainty concerning the safety of TRT, we have conducted a large retrospective study with long-term follow-up to address this knowledge gap. The objective of our study was to examine the association between TRT with documented normalization of total testosterone (TT) levels and all-cause mortality and adverse CV events defined by MI and stroke.
Abstract and Introduction
Abstract
Aims There is a significant uncertainty regarding the effect of testosterone replacement therapy (TRT) on cardiovascular (CV) outcomes including myocardial infarction (MI) and stroke. The aim of this study was to examine the relationship between normalization of total testosterone (TT) after TRT and CV events as well as all-cause mortality in patients without previous history of MI and stroke.
Methods and results We retrospectively examined 83 010 male veterans with documented low TT levels. The subjects were categorized into (Gp1: TRT with resulting normalization of TT levels), (Gp2: TRT without normalization of TT levels) and (Gp3: Did not receive TRT). By utilizing propensity score-weighted Cox proportional hazard models, the association of TRT with all-cause mortality, MI, stroke, and a composite endpoint was compared between these groups. The all-cause mortality [hazard ratio (HR): 0.44, confidence interval (CI) 0.42–0.46], risk of MI (HR: 0.76, CI 0.63–0.93), and stroke (HR: 0.64, CI 0.43–0.96) were significantly lower in Gp1 (n = 43 931, median age = 66 years, mean follow-up = 6.2 years) vs. Gp3 (n = 13 378, median age = 66 years, mean follow-up = 4.7 years) in propensity-matched cohort. Similarly, the all-cause mortality (HR: 0.53, CI 0.50–0.55), risk of MI (HR: 0.82, CI 0.71–0.95), and stroke (HR: 0.70, CI 0.51–0.96) were significantly lower in Gp1 vs. Gp2 (n = 25 701, median age = 66 years, mean follow-up = 4.6 years). There was no difference in MI or stroke risk between Gp2 and Gp3.
Conclusion In this large observational cohort with extended follow-up, normalization of TT levels after TRT was associated with a significant reduction in all-cause mortality, MI, and stroke.
Introduction
Professional guidelines recommend testosterone replacement therapy (TRT) in patients with signs and symptoms of hypogonadism and documented evidence of low testosterone (T) levels. The diagnosis of late-onset hypogonadism is on the rise with estimates that nearly 2.4 million men aged 40–69 suffer from hypogonadism in the USA. Even though late-onset hypogonadism is not a universally accepted concept, and FDA has advised against T supplementation in men on the basis of age alone. However, in the last decade there has been a nearly 400% increase in the number of TRT prescriptions creating a billion dollar market. With such widespread and ever increasing use of TRT, there has been growing concern regarding its effect on mortality and cardiovascular (CV) outcomes.
Recent retrospective studies, multiple meta-analyses, and a few small prospective studies have presented conflicting results and contributed to this uncertainty. Observational studies suggested that low serum T level is associated with increased CV events. Clinical trials examining TRT have been relatively small, and these trials were underpowered to provide conclusive evidence related to CV events. For instance, a small prospective study in frail elderly men showed an increased incidence of CV events with TRT and was stopped early. Two separate retrospective studies of men in the Veterans Affairs (VA) Health System using two different databases reported opposite effects of TRT on all-cause mortality. In two very recent studies, Vigen et al. using a VA database and Finkle et al. using a healthcare database reported that men receiving TRT had an increased risk of myocardial infarction (MI). It is important to note that in many of these studies repeat measurements to document normalization of T levels after TRT were lacking. On the heels of these recently published data, the FDA issued a drug safety alert related to TRT (http://www.fda.gov/Drugs/DrugSafety/ucm383904.htm).
In light of these conflicting results and uncertainty concerning the safety of TRT, we have conducted a large retrospective study with long-term follow-up to address this knowledge gap. The objective of our study was to examine the association between TRT with documented normalization of total testosterone (TT) levels and all-cause mortality and adverse CV events defined by MI and stroke.
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