PDE5 Inhibitors and Nitrates in Men With Ischemic Heart Disease

Quick Takes

  • The American Heart Association recommends that PDE5 inhibitors should not be given with nitrates, and nitrates can only be taken safely at least 24 and 48 hours after use of fast- and slow-acting PDE5 inhibitors, respectively. There are little data to support the guideline, but the results of the study may reflect the patient withholding the long-acting nitrate on the morning of or day prior to using the PDE5 inhibitor.
  • In a similar retrospective, observational study using prescription data from a large US-wide electronic health record database, the 3,167 patients with access to prescription copossession of PDE5 inhibitors and nitrates had no increase in rate of hypotensive/CV outcomes relative to those using prescription nitrates alone (with or without erectile dysfunction). In this study, only 27% of the 252 patients with adequate documentation were warned of coadministration at the time of coprescription.
  • There are data accumulating that suggest use of PDE5 inhibitors may reduce CV event rates in IHD. It is time for a randomized clinical trial.

Study Questions:

Has coprescription of nitrates and phosphodiesterase type 5 (PDE5) inhibitors changed, and what is the association between cardiovascular (CV) outcomes and coprescription of nitrates with PDE5 inhibitors?


This was a nationwide study from 2000–2018 in Danish male patients aged 30-85 years with a diagnosis of ischemic heart disease (IHD) prior to 2000 and a first-time diagnosis of IHD from 2000–2018 without prior nitrate use or continuing prescription for nitrates begun within 180 days from the date of event, and a new, filled prescription for PDE5 inhibitors. 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.


From 2000–2018, 249,541 male patients with IHD were identified. Of these, 42,073 patients had continuing prescriptions for nitrates (isosorbide mononitrate 21%; isosorbide dinitrate 78%); median age of 70 years; and a larger burden of comorbidity and concomitant treatment. The prescription rate for PDE5 inhibitors (total 91,838 with sildenafil 69%, tadalafil 27%) in those taking nitrates increased from an average of 0.9/100 persons/year in 2000 to 19.5 in 2018; and 3.1 to 31/100 persons/year in those not on nitrates. There was a total of 35,915 events. No statistically significant association was found between the crossover coprescription of nitrates with PDE5 inhibitors and the risk for either composite outcome (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.28-1.13 for the first outcome and OR, 0.73; 95% CI, 0.40-1.32 for the second outcome).


From 2000–2018, 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 CV adverse events could not be identified.


It is well known that erectile dysfunction is a risk marker for CV events. The increased use of PDE5 inhibitors in IHD with and without nitrates in the Danish findings are reassuring considering the size of the cohort, and that in year 2018, about 20% were prescribed nitrates (about 2,500 patients). The incremental use is likely related to the increase in quality of life and gradual willingness of physicians and patients to try it. Of course, patients on their own or with their physician’s suggestion may have held the long-acting nitrate in the morning with planned use in the evening or following day.

Clinical Topics: Arrhythmias and Clinical EP, Geriatric Cardiology, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Implantable Devices, SCD/Ventricular Arrhythmias, Statins, Interventions and Imaging, Interventions and Vascular Medicine, Angiography, Nuclear Imaging

Keywords: Angina Pectoris, Angiography, Brain Ischemia, Cyclic Nucleotide Phosphodiesterases, Type 5, Erectile Dysfunction, Geriatrics, Heart Arrest, Ischemic Stroke, Isosorbide Dinitrate, Myocardial Infarction, Myocardial Ischemia, Nitrates, Pharmaceutical Preparations, Phosphodiesterase 5 Inhibitors, Primary Prevention, Sildenafil Citrate, Stroke, Syncope, Tadalafil

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