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Co-prescribed PDE5 inhibitors and nitrates not tied to adverse outcomes

Annals of Internal Medicine
Reuters Health - 18/04/2022 - Patients with ischemic heart disease may be able to take ED medications along with oral organic nitrates without adverse events, a new study suggests.

Researchers analyzed data from 42,000 heart disease patients taking nitrates who were also prescribed a phosphodiesterase type 5 inhibitor for erectile dysfunction between 2000 and 2018. They found both that prescriptions for the ED medications had risen sharply during the studied years, and that there was no statistically significant association between co-prescription of nitrates with PDE5 inhibitors and adverse cardiovascular events, according to the results published in the Annals of Internal Medicine.

"Despite an absolute contraindication, co-prescription of PDE5 inhibitors for patients already on nitrate treatment has risen 20-fold from 2000 to 2018," said the study's first author, Dr. Anders Holt, a researcher in the department of cardiology at Copenhagen University Hospital–Herlev and Gentofte, Copenhagen, Denmark. "However, no increased risk following co-prescription was found, suggesting that in our selected cohort of patients, co-prescription could be safe."

Theoretically, co-prescription should raise the risk of cardiovascular events, Dr. Holt said in an email.

"Both nitrates and PDE5 inhibitors work by increasing cyclic guanosine monophosphate activity, thus relaxing smooth muscle cells in blood vessels, correspondingly relieving angina pectoris and erectile dysfunction," Dr. Holt said. "The effects are mediated by two different molecular pathways, augmenting the effect on blood pressure while inhibiting the body's own mitigation response. Accordingly, small randomized pharmacological studies have reported an amplified decrease in blood pressure during controlled co-exposure with nitrates and PDE5 inhibitors, both in healthy participants and in participants with ischemic heart disease. Potentially, in addition to acute dizziness and fainting, this increases the risk of vascular ischemic events including myocardial infarction and stroke due to, for example, hypoperfusion."

To explore how often co-prescription of nitrates and PDE5s leads to adverse events, Dr. Holt and his colleagues turned to Danish national health registers. The researchers included all male patients aged 30 to 85 who had a history of ischemic heart disease on January 1, 2000, or a first-time diagnosis of the condition during between 2000 and 2018, without prior nitrate use.

The researchers identified 249,541 patients, with a median age of 65, of whom, 42,073 received nitrates during follow-up. During the study period, the average yearly PDE5 prescription rate among all patients with ischemic heart disease increased by 10-fold, from an average of 3.1 to 30.9 prescriptions per 100,000 persons per year.

Similarly, in the subgroup of patients receiving nitrates, PDE5 prescriptions rose 20-fold, from 0.9 to 19.7 prescriptions per 100,000.

In this subgroup, there were 16,948 cases of cardiac arrest, shock, myocardial infarction, ischemic stroke and acute coronary arteriography during follow-up. However, when these cases were compared with an age-matched control group, researchers found no statistically significant increase in adverse cardiovascular events.

It's possible that drops in blood pressure occurred but did not lead to patients seeking treatment at the hospital, the authors note. It's also possible that patients were well informed about the risks or received guidance from their physicians, and paused nitrate use before initiating PDE5 use, or that they took the drugs at different times of the day, they write.

"Our results should not be interpreted as a recommendation of co-prescription for everyone, since we do not know the underlying explanation for co-prescription seemingly being safe in this selected cohort," Dr. Holt said. "A particular concern could be the known illegal drug import and distribution leading to PDE5 use without prior consultation."

The findings do not mean that it's safe to prescribe ED medications to patients with a nitrate prescription, said Dr. Matthew Tomey, an assistant professor of medicine and cardiology at the Icahn School of Medicine at Mount Sinai and a cardiologist at Mount Sinai Morningside in New York City.

"When interpreting this study, it is important to recognize that this is a retrospective look at registry data of patients who had concurrent prescriptions for nitrates and PDE5 inhibitors," Dr. Tomey said.

"This was not a randomized trial. We do not know whether the two medicines were in fact used concurrently or what counseling was given to patients. Selection bias is certain. Whereas this study captured major adverse events requiring hospitalization, it was not designed to ascertain adverse effects of concurrent use that did not result in hospitalization," Dr. Tomey added.

"As a practicing cardiologist, I remain very cautious about the concurrent use of nitrates and PDE5 inhibitors," Dr. Tomey said. "Together, these drugs can cause a marked drop in blood pressure. For some patients, this drop in blood pressure could be serious or even fatal. Contemplation of concurrent usage requires consultation with a cardiologist and careful consideration, counseling and monitoring. It is important to remember that we often have alternatives to long-acting nitrates and these can be considered if a patient requires a PDE5 inhibitor."

SOURCE: https://bit.ly/3xBGcdC and https://bit.ly/381WMZp Annals of Internal Medicine, online April 18, 2022.

By Linda Carroll

© 2023 The Author(s). Published by Medicom Medical Publishers.
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