madman
Super Moderator
Introductions
Cardiovascular diseases, including myocardial infarctions, and strokes, are major causes of mortality in the United States'. The development of these conditions is influenced by a combination of environmental, genetic, and lifestyle factors. Erectile dysfunction and lower urinary tract symptoms have both been linked to an increased risk of cardiovascular disease”. Effective management of these conditions is crucial for reducing morbidity and mortality’.
Phosphodiesterase-5 (PDE-5) inhibitors, such as tadalafil and sildenafil, have emerged as potential therapeutic agents for cardiovascular disease due to their ability to inhibit the degradation of cGMP in smooth muscle, leading to relaxation and improved blood flow’. They are believed to offer cardiovascular benefits through vasodilation, enhanced endothelial function,and improved sexual activity™®. These medications are FDA-approved for treating erectile dysfunction, idiopathic pulmonary hypertension, and lower urinary tract symptoms associated with benign prostatic hyperplasia®.
Research has explored the cardiovascular benefits of PDE-5 inhibitors, with several smaller studies indicating that these medications may reduce cardiovascular complications and mortality in patients with erectile dysfunction”. However, many of these studies focused on specific populations, such as those with type 2 diabetes*®. Retrospective longitudinal analyses have suggested that PDE-5 inhibitors may lower the incidence of major adverse cardiovascular events (MACE), mortality, and venous thromboembolisms; however, no clear comparisons between doses were assessed””!°. Evidence from animal models and retrospective studies also hints at cognitive benefits, but large-scale clinical trials are lacking''!?.
This longitudinal study aims to evaluate the effects of tadalafil and sildenafil on all-cause mortality, and the development of myocardial infarction, cerebrovascular accidents (stroke), venous thromboembolism, and dementia over a 3 year follow-up period using a large, real-world data base.
Strengths and Limitations
The strengths of this study include the large cohort size, which is significantly larger than those in prior studies, the use of propensity matching to control for confounders, the utilization of data from a large, real-world database encompassing healthcare organizations across the US,and the practical implications of using relatively inexpensive medications to reduce mortality,improve cardiovascular outcomes, and lower the risk of dementia. The follow up for mortality is excellent in this database, as 94% of sites are linked to the death registries in the US. The follow up for the other outcomes could be missing if an individual sought subsequent healthcare outside of the HCOs and this is a potential limitation of this study.
This retrospective database review from multiple HCOs establishes correlations but cannot infer causality. While propensity matching accounted for diabetes mellitus, kidney failure, obesity, cardiac conditions, malignancies, COPD, and hypertension, other diseases and socioeconomic factors may not have been fully controlled. The TriNetX database has limitations in capturing comprehensive demographic factors and pre-existing conditions, which may affect the findings.
Socioeconomic factors, such as Medicaid coverage limitations on lifestyle drugs, could influence medication affordability*®. Our post hoc analysis suggests these factors have minimal impact with only a 1-4% difference in relative risks. The study does not address side effects like headaches, flushing, angina, or priapism, and we cannot determine if medications were discontinued due to these effects. Additionally, since both tadalafil and sildenafil are processed by the CYP450 system, interactions with other medications or dietary supplements could confound results”.
TriNetX, relying on EHR and insurance claim data, may have misclassification bias. The database does not track patient compliance with medications, which is crucial for chronic therapies like tadalafil. There is also uncertainty about whether tadalafil 5 mg was used as intended for chronic therapy.
The study focused on males due to FDA approval and prescription guidelines for erectile dysfunction and lower urinary tract symptoms. However, off-label use in females exists,suggesting potential cardioprotective benefits for them.as well. Future research should explore outcomes such as all-cause mortality, myocardial infarction, stroke, and venous thromboembolism risk in females prescribed tadalafil.
Conclusion
Males 40 years of age and older with erectile dysfunction taking tadalafil experienced significant reductions in all-cause mortality, myocardial infarction, stroke, venous thromboembolism, and dementia compared to those not on the medication. Both tadalafil and sildenafil provided benefits, with tadalafil showing more favorable outcomes. In patients with lower urinary tract symptoms, tadalafil also demonstrated significant benefits. In the clinical treatment of patients, 5 mg daily dosing of tadalafil should be considered for all individuals with erectile dysfunction, or lower urinary tract symptoms. Further research is needed to explore the effects of low-dose tadalafil in patients with cardiovascular diseases and dementia risk, and randomized controlled trials should be conducted to establish causation between PDE-5 inhibitors and reductions in mortality, cardiovascular diseases, and dementia.
Cardiovascular diseases, including myocardial infarctions, and strokes, are major causes of mortality in the United States'. The development of these conditions is influenced by a combination of environmental, genetic, and lifestyle factors. Erectile dysfunction and lower urinary tract symptoms have both been linked to an increased risk of cardiovascular disease”. Effective management of these conditions is crucial for reducing morbidity and mortality’.
Phosphodiesterase-5 (PDE-5) inhibitors, such as tadalafil and sildenafil, have emerged as potential therapeutic agents for cardiovascular disease due to their ability to inhibit the degradation of cGMP in smooth muscle, leading to relaxation and improved blood flow’. They are believed to offer cardiovascular benefits through vasodilation, enhanced endothelial function,and improved sexual activity™®. These medications are FDA-approved for treating erectile dysfunction, idiopathic pulmonary hypertension, and lower urinary tract symptoms associated with benign prostatic hyperplasia®.
Research has explored the cardiovascular benefits of PDE-5 inhibitors, with several smaller studies indicating that these medications may reduce cardiovascular complications and mortality in patients with erectile dysfunction”. However, many of these studies focused on specific populations, such as those with type 2 diabetes*®. Retrospective longitudinal analyses have suggested that PDE-5 inhibitors may lower the incidence of major adverse cardiovascular events (MACE), mortality, and venous thromboembolisms; however, no clear comparisons between doses were assessed””!°. Evidence from animal models and retrospective studies also hints at cognitive benefits, but large-scale clinical trials are lacking''!?.
This longitudinal study aims to evaluate the effects of tadalafil and sildenafil on all-cause mortality, and the development of myocardial infarction, cerebrovascular accidents (stroke), venous thromboembolism, and dementia over a 3 year follow-up period using a large, real-world data base.
Strengths and Limitations
The strengths of this study include the large cohort size, which is significantly larger than those in prior studies, the use of propensity matching to control for confounders, the utilization of data from a large, real-world database encompassing healthcare organizations across the US,and the practical implications of using relatively inexpensive medications to reduce mortality,improve cardiovascular outcomes, and lower the risk of dementia. The follow up for mortality is excellent in this database, as 94% of sites are linked to the death registries in the US. The follow up for the other outcomes could be missing if an individual sought subsequent healthcare outside of the HCOs and this is a potential limitation of this study.
This retrospective database review from multiple HCOs establishes correlations but cannot infer causality. While propensity matching accounted for diabetes mellitus, kidney failure, obesity, cardiac conditions, malignancies, COPD, and hypertension, other diseases and socioeconomic factors may not have been fully controlled. The TriNetX database has limitations in capturing comprehensive demographic factors and pre-existing conditions, which may affect the findings.
Socioeconomic factors, such as Medicaid coverage limitations on lifestyle drugs, could influence medication affordability*®. Our post hoc analysis suggests these factors have minimal impact with only a 1-4% difference in relative risks. The study does not address side effects like headaches, flushing, angina, or priapism, and we cannot determine if medications were discontinued due to these effects. Additionally, since both tadalafil and sildenafil are processed by the CYP450 system, interactions with other medications or dietary supplements could confound results”.
TriNetX, relying on EHR and insurance claim data, may have misclassification bias. The database does not track patient compliance with medications, which is crucial for chronic therapies like tadalafil. There is also uncertainty about whether tadalafil 5 mg was used as intended for chronic therapy.
The study focused on males due to FDA approval and prescription guidelines for erectile dysfunction and lower urinary tract symptoms. However, off-label use in females exists,suggesting potential cardioprotective benefits for them.as well. Future research should explore outcomes such as all-cause mortality, myocardial infarction, stroke, and venous thromboembolism risk in females prescribed tadalafil.
Conclusion
Males 40 years of age and older with erectile dysfunction taking tadalafil experienced significant reductions in all-cause mortality, myocardial infarction, stroke, venous thromboembolism, and dementia compared to those not on the medication. Both tadalafil and sildenafil provided benefits, with tadalafil showing more favorable outcomes. In patients with lower urinary tract symptoms, tadalafil also demonstrated significant benefits. In the clinical treatment of patients, 5 mg daily dosing of tadalafil should be considered for all individuals with erectile dysfunction, or lower urinary tract symptoms. Further research is needed to explore the effects of low-dose tadalafil in patients with cardiovascular diseases and dementia risk, and randomized controlled trials should be conducted to establish causation between PDE-5 inhibitors and reductions in mortality, cardiovascular diseases, and dementia.
