Copenhagen, Denmark—The FDA and other international regulatory groups have made it clear that the concomitant use of oral organic nitrates (nitrates) and PDE5Is is contraindicated due to concerns of excessive preload reduction.

That can occur in patients who initiate PDE5Is while using long-acting nitrates like isosorbide mononitrate, isosorbide dinitrate, and transdermal nitroglycerin patches as prophylaxis for chronic angina. The American College of Cardiology has recommended that patients taking PDE5Is wait for at least 1 to 2 days after the last PDE5I dose before administering nitrates.

So, why was a Danish study looking at the issue unable to identify a "statistically significant association between concomitant use of these medications and cardiovascular adverse events?" University of Copenhagen–led researchers pointed out in Annals of Internal Medicine that from 2000 to 2018, the use of PDE5Is increased 20-fold among Danish patients with ischemic heart disease (IHD) who were taking nitrates.

The study team sought to measure trends over time in the coprescription of nitrates and PDE5Is, as well as to quantify the association between cardiovascular outcomes and the use of nitrates together with PDE5Is.

Using a case-crossover design, researchers conducted a nationwide study of Danish patients from 2000 to 2018. Included were male patients with International Classification of Diseases, 10th Revision codes for IHD, including those who had a continuing prescription for nitrates and a newly filled prescription for PDE5Is.

The researchers measured two composite outcomes: cardiac arrest, shock, myocardial infarction, ischemic stroke, or acute coronary arteriography; and syncope, angina pectoris, or drug-related adverse event.

Using the data, the study team identified 249,541 male patients with IHD; of those, 42,073 patients had continuing prescriptions for nitrates.

"During this period, the prescription rate for PDE5Is 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," the study noted.

Yet, the authors advised that no statistically significant association was determined between the concurrent prescribing of nitrates with PDE5Is and the risk for either composite outcome (odds ratio [OR], 0.58 [CI, 0.28-1.13] for the first outcome and OR, 0.73 [CI, 0.40-1.32] for the second outcome).

One limitation, according to the authors, is that an assumption was made that concurrently filled prescriptions for nitrates and PDE5Is equaled concomitant use.

In an effort to explain the outcomes, the authors wrote, "The unwanted outcomes that have been found in laboratory studies and clinical trials when these drugs are taken together may occur only infrequently in the real world when the 2 drugs are used in ordinary medical practice. One possible explanation is that doctors are advising patients to take the 2 drugs at different times of the day, and patients are following this advice."

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