Adverse Events Associated With Coprescription of Phosphodiesterase Type 5 Inhibitors and Oral Organic Nitrates in Male Patients With Ischemic Heart Disease: A Case-Crossover Study

Background: Concomitant use of oral organic nitrates (nitrates) and phosphodiesterase type 5 (PDE5) inhibitors is contraindicated. Objective: To measure temporal trends in the coprescription of nitrates and PDE5 inhibitors and to measure the association between cardiovascular outcomes and the coprescription of nitrates with PDE5 inhibitors. Design: Case-crossover design. Setting: Nationwide study of Danish patients from 2000 to 2018. Patients: Male patients with International Classification of Diseases, 10th Revision (ICD-10) codes for ischemic heart disease (IHD), including those who had a continuing prescription for nitrates and a new, filled prescription for PDE5 inhibitors. Measurements: Two composite outcomes were measured: 1) cardiac arrest, shock, myocardial infarction, ischemic stroke, or acute coronary arteriography and 2) syncope, angina pectoris, or drug-related adverse event. Results: From 2000 to 2018, 249 541 male patients with IHD were identified. Of these, 42 073 patients had continuing prescriptions for nitrates. During this period, the prescription rate for PDE5 inhibitors in patients with IHD who were taking nitrates increased from an average of 0.9 prescriptions (95% CI, 0.5 to 1.2 prescriptions) per 100 persons per year in 2000 to 19.5 prescriptions (CI, 18.0 to 21.1 prescriptions) in 2018. No statistically significant association was found between the coprescription of nitrates with PDE5 inhibitors and the risk for either composite outcome (odds ratio [OR], 0.58 [CI, 0.28 to 1.13] for the first outcome and OR, 0.73 [CI, 0.40 to 1.32] for the second outcome). Limitation: An assumption was made that concurrently filled prescriptions for nitrates and PDE5 inhibitors equaled concomitant use. Conclusion: From 2000 to 2018, the use of PDE5 inhibitors increased 20-fold among Danish patients with IHD who were taking nitrates. A statistically significant association between concomitant use of these medications and cardiovascular adverse events could not be identified.