Combining Nitrates With PDE5 Inhibitors for Patients With Cardiovascular Diseases Is Still a Risk

Since I’ve been a pharmacist, the adage has always been that combining nitrates with a PDE5 inhibitor (PDE5i) like sildenafil was a hard no. Most, if not all, pharmacists reading this article were likely taught the same. Combining nitrates with PDE5i can lead to a dangerous drop in blood pressure. I can still remember screening all the male patients with chest pain for recent PDE5i use on my emergency department rotation as a student. If they said “yes,” we avoided giving nitrates or did so very slowly and cautiously.

And despite this old dogma, numerous epidemiological studies published recently have shown that many clinicians are throwing caution to the wind and prescribing these drugs in combination.¹ To my surprise, and others in the cardiovascular community, these studies identified no associated harms with this combination.

Considering these counterintuitive findings, additional studies of this combination are warranted. In this week’s issue of Talking Therapeutics, we discuss a new paper addressing this key research question.

Talking Point: The Old Adage Seems True

In a new paper published in JACC, researchers evaluated the Swedish Patient Register and the Prescribed Drug Register, and included men with previous MI or revascularization who were prescribed both nitrates and a PDE5i. The primary outcomes of interest were all-cause, cardiovascular, and non-cardiovascular mortality, MI, heart failure, cardiac revascularization, and major cardiovascular events.

Unfortunately, the authors found that the combined use of PDE5i treatment with nitrates was associated with higher mortality (HR: 1.39; 95% CI: 1.28-1.51), cardiovascular mortality (HR: 1.34; 95% CI: 1.11-1.62), non-cardiovascular mortality (HR: 1.40; 95% CI: 1.27-1.54), MI (HR: 1.72; 95% CI: 1.55-1.90), heart failure (HR: 1.67; 95% CI: 1.48-1.90), cardiac revascularization (HR: 1.95; 95% CI: 1.78-2.13), and MACE (HR: 1.70; 95% CI: 1.58-1.83).

Talking Point: Trust the Experts

In this case, what we learned when we were “growing up” as junior pharmacists was true. These findings should reinforce the notion that pharmacists should not combine nitrates with PDE5is in men with stable coronary artery disease. I wish I had something positive to say regarding a treatment recommendation, but unfortunately, I don’t. The alternative treatments for anginal symptoms (beta-blockers in particular) are going to worsen symptoms of ED. Thus, substituting nitrates for an alternative medication in patients with ED is going to create a rather unfortunate cycle of misery for these patients.

Ultimately, for this drug interaction, we need science to discover an alternative treatment for ED, one that doesn’t interfere with the benefit of nitrates for patients with cardiovascular diseases.

Reference

Nunes AP, Seeger JD, Stewart A, Gupta A, McGraw T. Cardiovascular outcome risks in patients with erectile dysfunction co-prescribed a phosphodiesterase type 5 inhibitor (PDE5i) and a nitrate: a retrospective observational study using electronic health record data in the United States. J Sex Med. 2021;18:1511-1523. doi: 10.1016/j.jsxm.2021.06.010