madman
Super Moderator
Abstract
Introduction: The cardiovascular (CV) safety of testosterone replacement therapy (TRT) remains a crucial issue in the management of subjects with late onset hypogonadism. The authors systematically reviewed and discussed the available evidence focusing our analysis on heart related issues.
Areas covered: All the available data from prospective observational studies evaluating the role endogenous T levels on the risk of acute myocardial infarction (AMI) were collected and analyzed. In addition, the impact of TRT on heart related diseases, as derived from pharmaco-epidemiological studies as well as from randomized placebo controlled trials (RCTs), was also investigated.
Expert opinion:
Available evidence indicates that endogenous low T represents a risk factor of AMI incidence and its related mortality. TRT in hypogonadal patients is able to improve angina symptoms in subjects with ischemic heart diseases and exercise ability in patients with heart failure (HF). In addition, when prescribed according to the recommended dosage, TRT does not increase the risk of heart-related events.
Article highlights
• Low endogenous testosterone (T) is associated with an increased risk of acute myocardial infarction (AMI)-related mortality and AMI incidence.
• Testosterone replacement therapy (TRT) in hypogonadal patients is able to improve angina symptoms in subjects with ischemic heart diseases and exercise ability in patients with heart failure.
• In 2014, the European Medical Agency (EMA) did not share the FDA’s opinion of an increased CV risk linked to T medication, because of the lack of convincing evidence.
• The analysis of all randomized placebo controlled controlled trials showed that when prescribed according to the recommended dosage, TRT does not increase the risk of heart-related events.
4.0 Conclusions
The studies critically scrutinized here clearly show that low T is a marker of poor CV outcomes, including CAD. Meta-analysis of retrospective observational studies suggest that correcting T deficiency marginally improves cardiac outcomes. However, many of the weaknesses linked to pharmaco-epidemiological studies, here discussed, hamper confidence in this conclusion. Meta-analysis of interventional studies having cardiac outcomes as a primary end-point suggest an acute and chronic positive effect of TRT on increasing time to ST-segment depression and in some measures of HF. However, all these studies were of short duration and enrolling a limited number of subjects and therefore they are underpowered. In addition, they may have overlooked early positive transient effects. Nevertheless, prospective studies of longer duration enrolling hypogonadal subjects having cardiac safety as a primary end-point are difficult to realize, due to ethical reasons. For all these reasons, we here summarize in Forest plots results from different meta-analyses of available RCTs not having cardiac outcomes as an endpoint, but reporting information on them. Overall, included trials were of low-to-medium quality, enrolling subjects with variable characteristics, using different TRT protocols for various duration and, again, not powered to evaluate cardiac events. Meta-analysis is particularly useful when there are a variety of reports with low statistical power; thus, pooling data can improve power and provide a convincing result. All the different meta-analyses indicate that there is no significant risk for TRT in several cardiac outcomes, including AMI and acute coronary syndrome. It is important to recognize that all the available trials included in the meta-analyses have a relatively short duration, lasting at maximum three years. Therefore, although there is no clear sign of risk in the short term, no information is available on possible long-term effects. Considering that TRT is meant to be a lifelong treatment in the majority of cases the last issue is a relevant point. In conclusion, five years later, we fully endorse the EMA statement concerning TRT saying: “evidence regarding the risk of heart problems was inconsistent” (12). A new trial (TRAVERSE; clinicaltrials.gov, NCT03518034) to evaluate the effect of TRT on the incidence of MACE and efficacy measures in men with hypogonadism is ongoing. This is the first TRT trial with adequate power to assess CV events in hypogonadal population and it will give important information on this topic in the near future.
Important point for everyone to keep in mind!
* A new trial (TRAVERSE; clinicaltrials.gov, NCT03518034) to evaluate the effect of TRT on the incidence of MACE and efficacy measures in men with hypogonadism is ongoing. This is the first TRT trial with adequate power to assess CV events in hypogonadal population and it will give important information on this topic in the near future.
Introduction: The cardiovascular (CV) safety of testosterone replacement therapy (TRT) remains a crucial issue in the management of subjects with late onset hypogonadism. The authors systematically reviewed and discussed the available evidence focusing our analysis on heart related issues.
Areas covered: All the available data from prospective observational studies evaluating the role endogenous T levels on the risk of acute myocardial infarction (AMI) were collected and analyzed. In addition, the impact of TRT on heart related diseases, as derived from pharmaco-epidemiological studies as well as from randomized placebo controlled trials (RCTs), was also investigated.
Expert opinion:
Available evidence indicates that endogenous low T represents a risk factor of AMI incidence and its related mortality. TRT in hypogonadal patients is able to improve angina symptoms in subjects with ischemic heart diseases and exercise ability in patients with heart failure (HF). In addition, when prescribed according to the recommended dosage, TRT does not increase the risk of heart-related events.
Article highlights
• Low endogenous testosterone (T) is associated with an increased risk of acute myocardial infarction (AMI)-related mortality and AMI incidence.
• Testosterone replacement therapy (TRT) in hypogonadal patients is able to improve angina symptoms in subjects with ischemic heart diseases and exercise ability in patients with heart failure.
• In 2014, the European Medical Agency (EMA) did not share the FDA’s opinion of an increased CV risk linked to T medication, because of the lack of convincing evidence.
• The analysis of all randomized placebo controlled controlled trials showed that when prescribed according to the recommended dosage, TRT does not increase the risk of heart-related events.
4.0 Conclusions
The studies critically scrutinized here clearly show that low T is a marker of poor CV outcomes, including CAD. Meta-analysis of retrospective observational studies suggest that correcting T deficiency marginally improves cardiac outcomes. However, many of the weaknesses linked to pharmaco-epidemiological studies, here discussed, hamper confidence in this conclusion. Meta-analysis of interventional studies having cardiac outcomes as a primary end-point suggest an acute and chronic positive effect of TRT on increasing time to ST-segment depression and in some measures of HF. However, all these studies were of short duration and enrolling a limited number of subjects and therefore they are underpowered. In addition, they may have overlooked early positive transient effects. Nevertheless, prospective studies of longer duration enrolling hypogonadal subjects having cardiac safety as a primary end-point are difficult to realize, due to ethical reasons. For all these reasons, we here summarize in Forest plots results from different meta-analyses of available RCTs not having cardiac outcomes as an endpoint, but reporting information on them. Overall, included trials were of low-to-medium quality, enrolling subjects with variable characteristics, using different TRT protocols for various duration and, again, not powered to evaluate cardiac events. Meta-analysis is particularly useful when there are a variety of reports with low statistical power; thus, pooling data can improve power and provide a convincing result. All the different meta-analyses indicate that there is no significant risk for TRT in several cardiac outcomes, including AMI and acute coronary syndrome. It is important to recognize that all the available trials included in the meta-analyses have a relatively short duration, lasting at maximum three years. Therefore, although there is no clear sign of risk in the short term, no information is available on possible long-term effects. Considering that TRT is meant to be a lifelong treatment in the majority of cases the last issue is a relevant point. In conclusion, five years later, we fully endorse the EMA statement concerning TRT saying: “evidence regarding the risk of heart problems was inconsistent” (12). A new trial (TRAVERSE; clinicaltrials.gov, NCT03518034) to evaluate the effect of TRT on the incidence of MACE and efficacy measures in men with hypogonadism is ongoing. This is the first TRT trial with adequate power to assess CV events in hypogonadal population and it will give important information on this topic in the near future.
Important point for everyone to keep in mind!
* A new trial (TRAVERSE; clinicaltrials.gov, NCT03518034) to evaluate the effect of TRT on the incidence of MACE and efficacy measures in men with hypogonadism is ongoing. This is the first TRT trial with adequate power to assess CV events in hypogonadal population and it will give important information on this topic in the near future.
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