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Using nitrate and PDE5 inhibitors together not associated with a higher incidence of adverse CV events

Despite a contra-indication, the combined use of nitrate and PDE5 inhibitors does not appear to be linked to more adverse CV events

Using nitrates and phosphodiesterase type 5 (PDE5) inhibitors together does not seem to increase the risk of adverse cardiovascular (CV) outcomes, even though concomitant use of drugs from either class is contra-indicated. This was the key finding of a retrospective analysis by a team from the Research Division, Department of Cardiology, Herlev and Gentofte Hospital, Hellerup, Denmark.

Organic nitrates, which are vasodilators, are traditionally used for the treatment of angina and heart failure. Phosphodiesterase type 5 (PDE5) inhibitors are used for the treatment of erectile dysfunction but are also vasodilators and thus when taken together with nitrates, a synergistic effect occurs, enhancing the hypotensive effect of nitrates.

Moreover, in one study, co-administration of sildenafil (a PDE5 inhibitor) with either isosorbide mononitrate of glyceryl trinitrate produced significantly greater reductions in blood pressure than from either nitrate alone thereby confirming the possible adverse effect of using these drugs together.

In fact, in the summary of product characteristics for sildenafil, it states that ‘sildenafil was shown to potentiate the hypotensive effects of nitrates, and its co-administration with nitric oxide donors (such as amyl nitrite) or nitrates in any form is therefore contraindicated.’

In a 2019 review it was found that the global prevalence of erectile dysfunction was high, ranging from between 3 and 76.5%. Whilst the use of a nitrate and PDE5 inhibitors is a known contra-indication, given how erectile dysfunction is a common problem, the Danish researchers believed it likely that the two classes of drugs might be co-prescribed.

They set out to examine not only the extent of co-prescription of these drugs but also whether there was any evidence from a real-world setting, that this combination was associated with an increased level of adverse cardiovascular events.

Using a Danish national registry, the team identified male patients aged 30 to 85 years of age with a history of ischaemic heart disease and continued prescriptions for nitrates as well as a new prescription for a PDE5 inhibitor.

They considered two composite outcomes; one including cardiac arrest, shock, ischaemic stroke and a second which included angina, syncope and a diagnosis of an adverse drug-related event. These outcomes were primarily assessed within 14 days of PDE5 inhibitor exposure although 7, 21 and 28 days were also used because the exact time of PDE5 inhibitor use after filling a prescription was always going to be uncertain.

Nitrates and PDE5 inhibitors and adverse cardiovascular outcomes

A total of 249,541 men with ischaemic heart disease were identified, of whom 42,073, with a median age of 70 years, were prescribed oral nitrates. Between 2000 and 2018, the average yearly prescription rate for PDE5 inhibitors in those taking oral nitrates, increased from 0.9 to 19.7 per 100 persons per year.

In the subgroup of men prescribed oral nitrates, there were 16,948 cases of cardiac arrest, shock, myocardial infarction, ischaemic stroke or acute coronary arteriography during the follow-up period. However, there was no significant association between co-prescription of nitrates and PDE5 inhibitors (odds ratio, OR = 0.58, 95% CI 0.28 – 1.13) for a 14-day exposure window.

Similarly, for the second outcome, there was also no significant increased risk (OR = 0.73, 95% CI 0.40 – 1.32) during a 14-day exposure window. There were also no significant differences for 7, 21 and 28-day exposure windows.

Based on these findings, the authors concluded that despite the known contra-indication, there was no apparent increased risk of adverse cardiovascular events from co-prescription of nitrates and PDE5 inhibitors.

Holt A et al. 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 Ann Intern Med 2022