Cardiovascular Outcome Risks in Patients With Erectile Dysfunction Co-Prescribed a Phosphodiesterase Type 5 Inhibitor (PDE5i) and a Nitrate: A Retrospective Observational Study Using Electronic Health Record Data in the United States

Background: Phosphodiesterase type 5 inhibitors (PDE5i) are first-line therapy for erectile dysfunction (ED). Approximately 1-4% of PDE5i recipients co-possess nitrates, despite this combination potentially producing clinically significant hypotension. Real-world data in these patients and insights into prescriber rationales for co prescription are limited. Aim: This study investigated whether PDE5i and nitrate co-possession is associated with increased rates of cardiovascular (CV) outcomes. Methods: Adult males with ED and PDE5i prescription and males with nitrate prescription were identified from a U.S. electronic health record database (2012-2016). Quantitative comparisons were made between patients with ED and co-possession (ED + PDE5i + nitrate), only nitrate possession (ED + nitrate and nitrate only [without ED]), and only PDE5i possession (ED + PDE5i). Outcomes: We quantified incidence of CV outcomes in co-possession and comparator periods, calculating incidence rate ratios after propensity score matching. Prescriber rationales were derived by reviewing virtual patient records. Results: Over 168,000 patients had >1 PDE5i prescription (similar to 241,000 possession periods); >480,000 patients had >1 nitrate prescription (similar to 486,000 possession periods); and 3,167 patients had 3,668 co-possession periods. Non -significantly different or lower rates of CV outcomes were observed for co-possession periods vs ED + nitrate and nitrate only periods. Most CV outcome rates were non-significantly different between co-possession and ED + PDE5i periods (myocardial infarction, hospitalized unstable angina and fainting were higher with co-possession). From qualitative assessment of patient records with co-possession, 131 of 252 (52%) documented discussion with a physician regarding co-possession; 69 of 131 (53%) warned or instructed on safely managing these contraindicated medications. Clinical Implications: Findings from this real-world study indicate that co-possession of nitrate and PDE5i prescriptions is not associated with increased rates of CV outcomes, relative to possession of nitrates alone. Physicians should and often do discuss the risks of using both medications together with their patients. Strengths & Limitations: Strengths of this study are the large size of the U.S. real-world patient cohort with data available for analysis, and our ability to utilize natural language processing to explore co-prescription rationales and patient-physician interactions. Limitations are the retrospective nature of the analysis and inability to establish whether recorded prescriptions were filled or the medication was consumed. Conclusion: Co-exposure of PDE5i and nitrates should continue to be avoided; however, co-possession of PDE5i and nitrate prescriptions is not necessarily associated with increased CV risk. Co-possession can be successfully managed in suitable circumstances. Copyright (c) 2021 The Authors. Published by Elsevier Inc. on behalf of the International Society for Sexual Medicine.

Automated summary

This real-world study found that co-possession of nitrate and PDE5i prescriptions is not associated with an increased risk of cardiovascular outcomes. Most cardiovascular outcome rates were not significantly different between co-possession and ED + PDE5i periods, although some outcomes were higher with co-possession. Many patients discussed the risks of co-possession with their physicians and received warnings or instructions.