Why are pde5 inhibitors contraindicated with nitrates?

As coprescribing drugs for erectile dysfunction and oral organic nitrates for ischemic heart disease (IHD) surged, cardiovascular adverse events did not significantly increase, a new study finds.

The authors of the new research specifically examined how frequently phosphodiesterase type 5 (PDE5) inhibitors, such as Viagra, were prescribed. The U.S. Food and Drug Administration and the European Medicines Agency have warned that these drugs for erectile dysfunction are contraindicated for use with nitrates because of concerns about cardiovascular risks.

"Small, randomized, pharmacologic studies have reported an amplified decrease in blood pressure during controlled coexposure with nitrates and [phosphodiesterase type 5 inhibitors], both in healthy participants and in participants with IHD," wrote lead author Anders Holt, MD, of Copenhagen University Hospital–Herlev and Gentofte and colleagues, in Annals of Internal Medicine. "Potentially, this increases the risk for vascular ischemic events including myocardial infarction and stroke."

But there is a scarcity of real-world data showing that using both types of drugs together increases these risks, the researchers noted.

To address this knowledge gap, Holt and colleagues conducted a retrospective study involving 249,541 Danish men with IHD. In this overall population, from 2000 to 2018, prescriptions for PDE5 inhibitors increased 10-fold, from 3.1 to 30.9 prescriptions per 100 persons per year. Within a subgroup of 42,073 patients continuously prescribed oral organic nitrates, PDE5-inhibitor prescriptions jumped twice that magnitude, from 0.9 to 19.7 prescriptions per 100 persons per year.

Despite this surge in coprescribing, the investigators did not observe a significant increase in either of two composite measures of cardiovascular adverse events. The first composite included ischemic stroke, shock, cardiac arrest, myocardial infarction, or acute coronary arteriography (odds ratio, 0.58; 95% confidence interval, 0.28-1.13). The second composite included drug-related adverse events, angina pectoris, or syncope (OR, 0.73; CI, 0.40-1.32).

Lead Author Speculates on Reasons for Findings

"I propose several explanations [for these findings]," Holt said in an interview, "but I want to emphasize that our study does not contain any data to back it up. It is just speculation. First, the observed drop in blood pressure may not cause a condition for which patients seek a hospital. A drop in blood pressure has been shown in pharmacologic trials, but it might not translate to a real-life risk for cardiovascular outcomes. Second, patients could be well informed and adherent to guidance that the prescribing physician has provided. For example, patients are aware of the recommended pause in nitrate treatment before PDE5-inhibitor use and follow these recommendations. Third, nitrates are often taken in the morning, and with the careful assumption that most PDE5-inhibitor activities take place in the evening, the nitrates could be metabolized to a degree such that the synergistic interaction is negligible."

Holt went on to suggest a novel clinical approach based on the new findings.

"Coadministration should still be contraindicated due to the proven drop in blood pressure," he said. "However, perhaps physicians can allow for coprescription if patients are adequately informed."

A qualitative study is needed to determine how patients and physicians discuss coprescription, including avoidance of coadministration, Holt added.

Findings Call for a Reassessment of Whether the Contraindication is Warranted

Robert A. Kloner, MD, PhD, chief science officer and director of cardiovascular research at Huntington Medical Research Institutes in Pasadena, Calif., and professor of medicine at University of Southern California, Los Angeles, previously conducted research exploring drug interactions with PDE5 inhibitors, and in 2018, coauthored a literature review that concluded that PDE5 inhibitors and nitrates are contraindicated.

But now, considering these new findings, Kloner is offering a fresh perspective.

"This study is reassuring," Kloner said in an interview. "I think that it's time to reassess whether there should be an absolute contraindication, or this should be more of like a warning."

He noted that in controlled studies, like the ones he previously conducted, PDE5 inhibitors and nitrates were administered "very close to each other, on purpose," yet this probably doesn't reflect typical practice, in which clinicians can guide usage based on durations of drug metabolism.

"I think that physicians might be more comfortable now prescribing the drugs at the same time, but then telling patients that they shouldn't take the two drugs simultaneously; they should wait and take the nitrate 24 hours after the last Viagra, or the nitrate 48 hours after the last Cialis," Kloner said. "I suspect that that is happening. I suspect also the fact that people would be more likely to take the nitrate in the morning and the PDE5 inhibitor at night probably also contributes to the safety findings."

Kloner noted that blood pressures vary throughout the day based on circadian rhythm, and that the body can adapt to some fluctuations without negative effects.

There could still be some people who experience a drop in blood pressure and get sick from it from the two drugs interacting, but that's probably not that common, he said.

The study was supported by several grants. The investigators disclosed relationships with Merck, BMS, Bayer, and others. Kloner consults for Sanofi.

This story originally appeared on MDedge.com, part of the Medscape Professional Network.

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The combination of nitrates (and drugs such as nicorandil) with sildenafil is contraindicated. This combination must be avoided as it can produce significant hypotension and is potentially fatal.

The guidance from the Committee on Safety of Medicines (CSM) regarding nitrates and sildenafil states (1):

• sildenafil and nitrates - it is stated that these should not be used concurrently. This is because of the risk of severe hypotension. Nitrates are stated as those used for cardiovascular disease, e.g. GTN spray, and also recreational compounds e.g. amyl nitrate
• sildenafil should not be used in men for whom sexual activity is inadvisable e.g. patients with severe cardiovascular disorders such as severe heart failure or unstable angina

The British Heart Foundation have addressed the use of GTN spray and nitrate tablets and phosphodiesterase (PDE5) inhibitors (sildenafil, tadalafil, verdenafil) (2):

• nitrate therapy is an absolute contraindication to PDE5 inhibitors (1,2,3)
  • combination of nitrates with PDE5 inhibitors can produce unpredictable excess vasodilation, leading to profound hypotension - same risk also applies with nicorandil
    • if hypotension does occur then the patient should be placed in the Trendelenburg position and emergency help sought. Resuscitation with intravenous fluids should be initiated as soon as possible.
  • sublingual nitrates e.g. GTN spray should not be used within 24 hours of taking sildenafil or vardenafil and within 48 hours of taking tadalafil
    • note though that coital angina is not common and nitrates can often be safely discontinued or substituted in stable patients
    • if a patient has stable angina and erectile dysfunction then a reassessment of the need for nitrates should be undertaken before denying treatment with a PDE5 inhibitor
  • if a patient with CHD (and also taking a PDE5 inhibitor) develops angina during sexual activity, he must discontinue immediately and relax for 5-10 minutes. If he stands up then this will reduce the preload and may relieve symptoms.
    • if the angina pain does not resolve after 20-30 minutes the emergency services should be called informing them of the PDE5 inhibitor use - also sex should not be attempted again before the patient has undergone a thorough reassessment (2)

The concurrent use of nicorandil and PDE5 inhibitors is also contraindicated (2,3) - this is due to the nitrate component of nicorandil.

alpha blockers

• although PDE5Is are safe with most antihypertensive agents, coadministration with nitrates or alpha-blockers poses a risk of severe hypotension (4,5)
• all alpha-blockers can cause vasodilation and orthostatic hypotension, and coadministration with PDE5Is increases the risk of a clinically significant decrease in BP (5)
• only after patients are on stable alpha-blocker therapy should PDE5Is be initiated, starting with a low dose (5)

Referral to specialist is appropriate if severe CVD which makes sexual activity unsafe or a situation when PDE5 inhibitor use contra- indicated (6)

• from a therapeutical point of view, intracavernous injections of PGE1 (alprostadil) are efficient and safe second line in the treatment of erectile dysfunction in the cardiac population, whatever the origin. No drug interactions with the various treatment used in cardiology, notably derived nitrates, has been reported
• other treatment options include vacuum devices, insertion of transurethral alprostadil (MUSE), intracavernosal alprostadil (Caverjet)

Notes:

• nitrates are contraindicated within 24 hours of sildenafil and vardenafil and within 48 hours of tadalafil. Only after patients are on stable alph-blocker therapy should PDE5Is be initiated, starting with a low dose
• potent cytochrome P450 3A4 inhibitors, including erythromycin, clarithromycin, ketoconazole, itraconazole, and HIV protease inhibitors, increase PDE5I plasma concentrations. PDE5I drug interactions have the potential to cause life-threatening hypotension in patients with coexisting cardiac disease requiring nitrates or alpha blockers (5)
• "uroselective" alpha-blockers (tamsulosin, alfuzosin) preferentially inhibit alpha 1A and alpha 1D receptors found primarily in the prostate and benefit patients with benign prostatic hypertrophy. Other alpha-blockers (terazosin) are less selective, and some (doxazosin) are used as third-line agents for hypertension because of their higher affinity for alpha -1B receptors, which are abundant in the peripheral vasculature (5)

Reference:

Last reviewed 01/2018

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