Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: A retrospective, observational study based on healthcare claims and national death index data

Abstract

Background Treatment with phosphodiesterase type 5 inhibitors (PDE-5is) is effective in treating erectile dysfunction (ED). Aim The objective of this study was to determine the effect of PDE-5is on the incidence of major adverse cardiovascular (CV) events (MACE; composite outcome of CV death, hospitalization for myocardial infarction, coronary revascularization, stroke, heart failure, and unstable angina pectoris) and overall mortality. Methods A retrospective observational cohort study was conducted in a large US claims database in men with ≥1 diagnosis of ED without prior MACE within 1 year, from January 1, 2006, to October 31, 2020. The exposed group had ≥1 claim for PDE-5i and the unexposed group had no claims for PDE-5i, and the groups were matched up to 1:4 on baseline risk variables. Outcome The primary outcome was MACE and the secondary outcomes were overall mortality and individual components of MACE, determined by multivariable Cox proportional hazard modeling. Results Matched plus multivariable analyses showed that MACE was lower by 13% in men exposed (n = 23 816) to PDE-5is (hazard ratio [HR] 0.87; 95% CI 0.79-0.95; P = .001) vs nonexposure (n = 48 682) over mean follow-up periods of 37 and 29 months, respectively, with lower incidence of coronary revascularization (HR 0.85; 95% CI 0.73-0.98; P = .029), heart failure (HR 0.83; 95% CI 0.72-0.97; P = .016), unstable angina (HR 0.78; 95% CI 0.64-0.96; P = .021), and CV death (HR 0.61; 95% CI 0.41-0.90; P = .014) with PDE-5i exposure. Phosphodiesterase type 5 inhibitor–exposed men had a 25% lower incidence of overall mortality (HR 0.75; 95% CI 0.65-0.87; P < .001). Men without coronary artery disease (CAD) but with CV risk factors at baseline showed a similar pattern. In the main study cohort, men in the highest quartile of PDE-5i exposure had the lowest incidence of MACE (HR 0.45; 95% CI 0.37-0.54; P < .001) and overall mortality (HR 0.51; 95% CI 0.37-0.71; P < .001) vs the lowest exposure quartile. In a subgroup with baseline type 2 diabetes (n = 6503), PDE-5i exposure was associated with a lower MACE risk (HR 0.79; 95% CI 0.64-0.97; P = .022). Clinical Implications PDE-5is may have cardioprotective effects. Strengths and Limitations Strengths are the large numbers of participants and consistency of the data; limitations include the retrospective nature of the study and unknown confounders. Conclusions In a large population of US men with ED, PDE-5i exposure was associated with lower incidence of MACE, CV death, and overall mortality risk compared to non-exposure. Risk reduction correlated with PDE-5i exposure level.

The increasing role of PDE5Is in men with diabetes and cardiovascular disease

“…PDE5Is are first‐line agents in treatment for erectile dysfunction, and importantly, longitudinal studies suggest that PDE5Is reduce all‐cause mortality in men with T2DM, previous myocardial infarction, erectile dysfunction (Figure 1) and benign prostatic hypertrophy (BPH). A review of PDE5Is and all‐cause mortality (excluding pulmonary hypertension and heart failure) identified five recent studies 8,9–12 . These studies show a significant reduction in all‐cause mortality and morbidity associated with PDE5I use in men with T2DM, the general population and men with lower urinary tract symptoms (LUTS).…”

“…observed a 13% lower incidence of MACE, 25% reduction in all‐cause mortality and 39% reduction in cardiovascular mortality, in those exposed to PDE5I medications. The authors called for urgent studies to assess risk reduction in randomised controlled trials 8 …”

“…Adjusted survival curves showing the effect on overall mortality in men with erectile dysfunction treated with phosphodiesterase type 5 inhibitor (PDE5I) compared with controls not treated with PDE5I 8 …”

“…A review of PDE5Is and all-cause mortality (excluding pulmonary hypertension and heart failure) identified five recent studies. 8,[9][10][11][12] These studies show a significant reduction in all-cause mortality and morbidity associated with PDE5I use in men with T2DM, the general population and men with lower urinary tract symptoms (LUTS).…”

“…The authors called for urgent studies to assess risk reduction in randomised controlled trials. 8 Despite these findings, prescribing of PDE5Is is often avoided in higher risk patients and dosing is still often restricted to one tablet on-demand per week.…”