The Impact of Sildenafil on Ischemic Outcomes in Patients with Pulmonary Hypertension - A Nationwide Cohort Study

Background: Sildenafil, a phosphodiesterase-5 inhibitor, has been approved for the treatment of pulmonary hypertension (PH). It improves exercise capacity, symptoms and hemodynamics in patients with PH by lowering pulmonary pressures. Preclinical studies have indicated a possible protective effect of sildenafil on ischemia/ reperfusion injury. Nevertheless, evidence showing the impact of sildenafil on ischemic disorders in patients with PH is lacking.Methods: Using the Taiwanese National Health Insurance Research Database and Cause of Death databases, we conducted a retrospective cohort study to investigate the hazard ratio (HR) with inverse probability of treatment weighting (IPTW) of sildenafil for the development of major adverse cardiovascular and cerebrovascular events (MACCEs), including new-onset acute myocardial infarction (AMI) and ischemic stroke in patients with PH. The follow-up period was 7 years. In addition, we performed sensitivity analysis by limiting the studied population to those who received right heart catheterization and excluding those with a history of coronary arterial disease.Results: After adjusting for age, sex and comorbidities, the patients receiving sildenafil had a significantly lower risk of subsequent AMI [adjusted HR with IPTW: 0.42; confidence interval (CI): 0.20-0.86] and a trend of less ischemic stroke (adjusted HR with IPTW: 0.72; CI: 0.51-1.02). Interestingly, among the sildenafil users, those who were older, had chronic kidney disease, and took cardiovascular medications showed the most significant reductions in the risk of MACCEs. The sensitivity analysis showed similar results.Conclusions: The use of sildenafil in patients with PH was associated with a lower risk of long-term MACCEs. More evidence is needed to validate our findings.